Cytokines: Names and Numbers You Should Care About

Stephen R. Holdsworth*† and Poh-Yi Gan*

Abstract
Cytokines play an important role in host defense against microorganisms. They orchestrate innate immunity by
inducing protective local inflammation and systemic acute phase responses. Cytokines are important in initiating,
amplifying, directing, mediating, and regulating adaptive immunity. Unfortunately, they may also direct tissue
damage if excessive responses occur or if they are involved in directing and mediating autoimmunity. Under these *Center for
circumstances, cytokines are potential therapeutic targets. Over the last 20 years, we have seen the successful Inflammatory
development and clinical implementation of biologic strategies that target key cytokines in specific inflammatory Diseases, Department
diseases with efficacy, specificity, and toxicity profiles challenging conventional drug therapies. These therapies of Medicine, Monash
University, Clayton,
are finding new applications and many new agents show promise. Unfortunately, these new cytokine-based Victoria, Australia;
therapies have had little effect on renal disease. This review provides evidence that common renal diseases, and †Department of
including those causing AKI and the autoimmune proliferative and crescentic forms of GN, have cytokine Nephrology, Monash
mediation profiles that suggest they would be susceptible to cytokine-targeting therapeutic strategies. Health, Clayton,
Victoria, Australia
Clin J Am Soc Nephrol 10: 2243–2254, 2015. doi: 10.2215/CJN.07590714
Correspondence:
Prof. Stephen R.
Introduction colony stimulating factors (granulocyte colony–stimulating Holdsworth, Centre
Cytokines amplify and direct the generation of ap- factor [G-CSF] and granulocyte–macrophage colony– for Inflammatory
propriate patterns of immunity to combat particular stimulating factor [GM-CSF]), and some growth factors Diseases, Department
of Medicine, Monash
microbial threats. These same cytokines can cause host (TGF-b and PDGF). University, Monash
tissue injury if the activation/amplification of host Medical Centre, 246
defense is overexuberant, as occurs in some infective Clayton Road,
and sterile forms of inflammation. These pathologic Clayton, VIC 3168,
Cytokines in Host Defense Australia. E-mail:
cytokine-driven outcomes are seen in many types of Innate Immunity Stephen.holdsworth@
AKI caused by physical, drug, chemical, and ischemic Most living organisms rely on innate immunity (in monash.edu
injury. If immune tolerance is lost and host tissue the absence of adaptive immunity) for host defense.
antigens become autoimmune targets, cytokines can Cytokines play critical roles in orchestrating the rapid
direct and mediate inflammatory autoimmune dis- effective response of leukocytes and parenchymal
eases. Important renal examples are the autoimmune cells to the detection of microorganisms or significant
forms of inflammatory/crescentic GN. Cytokines act in noninfective damage to parenchymal cells. These cells
concert to generate inflammation in host defense and are hardwired with receptors that recognize and re-
disease, but some cytokines attenuate inflammation and spond to common pathogen proteins through Toll-like
induce repair. Individual cytokines can be inhibited by receptors (TLRs) and danger-associated molecular pat-
antibodies or competitive receptors or by the therapeu- tern receptors (1). Although leukocytes are the major
tic use of immunomodulatory cytokines. These biologic source of innate cytokine responses, parenchymal cells
agents are now widely used to treat inflammatory are increasingly recognized as also producing innate
diseases. There are a number of common renal diseases inflammatory cytokines and interacting with leuko-
that could potentially be treated by targeting cytokines. cytes to optimize cytokine responses in generating
This review will address these issues. host defense. The major acute innate cytokines, IL-1,
TNF-a, IL-6, IL-12, CXCL8 (formerly IL-18), G-CSF,
Cytokine Nomenclature and GM-CSF, are used locally to activate endothelial
Cytokines are glycoproteins that regulate the functions cells and local tissue leukocytes (mast cells [MCs], den-
of the immune system. Definitions are imprecise because dritic cells [DCs], gd T cells, and neurones), triggering
of redundancy of function and the capacity of tissue cytokine-mediated amplification loops generating che-
parenchymal cells and leukocytes to produce them. mokine release, generating endothelial cell adhesion
Hence the terms lymphokine and monokine have been molecule expression, slowing blood flow, and increas-
dropped. Originally described by their perceived major ing vascular permeability. These changes facilitate the
function, the term IL has been adopted. When an agreed accumulation of humoral defense proteins, comple-
characterization of a cytokine is broadly accepted, a ment, coagulation proteins, acute phase proteins, and
number is attributed (e.g., IL-6). However, the use of Ig. They also recruit and activate a range of leukocytes
descriptive names for some key cytokines persists, in- (including innate lymphocytes, gd T cells, natural killer
cluding IFNs (a, b, and g), TNF (TNF-a and TNF-b), cells, natural killer T cells [NKT] cells, and innate

www.cjasn.org Vol 10 December, 2015 Copyright © 2015 by the American Society of Nephrology 2243
2244 Clinical Journal of the American Society of Nephrology

leukocyte-like cells). The net result of these orchestrated transcription factors STAT6 and GATA3 producing IL-4,
events is inflammation. Concurrently, two further processes IL-5, IL-9, and IL-13 that drives humoral and IgE mediated
are initiated: a cohort of cytokines (IL-1, IL-6, and TNF-a) are immunity. In 2005, a new distinct Th subset was defined on
generated that act systemically to prepare the whole organ- the basis of its predominant production of IL-17, named
ism for microbial defense by initiating the acute response Th17 cells (4). Lineage commitment of Th17 cells requires
syndrome (2) and local foreign material is processed and TGF-b and IL-6 for the expression of the transcription fac-
presented by antigen-presenting cells (APCs) to initiate tors, STAT3 and RORg-t, whereas maintenance and expan-
adaptive immunity. These secondary processes are also crit- sion of Th17 cells relies on IL-23. Activated Th17 cells
ically dependent on cytokine direction and are also respon- produce IL-17A-F, IL-21, IL-23, and IL-22 and activate cells,
sive to inhibitory cytokine modulation (Figure 1). particularly neutrophils, important in host defense against
extracellular pathogens. Antigen presentation by TGF-b
alone activates Foxp3-inducing regulatory T cells (Tregs),
Adaptive Immunity
CD41 T cells play a central role in adaptive immunity producing IL-10, TGF-b, and IL-35. Tregs play an impor-
which is characterized by antigen specificity and memory/ tant role in modulating effector T-cell responses and pre-
recall capacity. T-cell specificity is a consequence of the di- venting autoimmunity.
versity of T cell receptors (TCRs) from which thymic pro- Three further Th subsets have been defined: Th9, Th22,
cessing eliminates potentially autoreactive T cells to form the and T follicular helper. The Th2 subset is reprogrammed to
T-cell repertoire. Antigen recognition (signal 1) is initiated by become Th9 when IL-4 plus TGF-b activates STAT6, IRF4,
TCR binding to antigens ingested, processed, and presented GATA3, and PU.1 to produce IL-9, IL-10, IL-17, IL-21, and
(as peptides) on major histocompatibility complex molecules IL-22, promoting tissue inflammation (5). Th22 is important
by specialized APCs. Activation of T cells requires secondary in skin immunity (protection and regeneration). TGF-a and
signals provided by costimulatory molecules (including IL-6 activates transcription factor, AHR, to direct the differ-
CD40, CD80, and CD86) expressed on APCs to engage entiation of IL-22, producing Th22 cells. T follicular helper
CD154 or CD28 on T cells. Innate cytokines released at cells migrate to follicular B-cell zones via CXCR5 where they
the time of antigen presentation (a third signal) deter- help B cells activating Bcl-6 to produce IL-21 (6) (Table 1).
mine the specific Th subset differentiation pathway the
(now activated) T cells will follow. In 1986, Mossman and Cytokines as Therapeutic Targets
Coffman demonstrated that there were two separate path- Many conventional immunomodulating drugs induce their
ways of Th subset differentiation, Th1 and Th2 (3). Th1 therapeutic effects, at least in part, by attenuating the actions
lineage commitment is directed by IL-12, which induces the of injurious cytokines. These drugs include glucocorticoids.
specific signal transducers and activators of transcription Their targets include transcription factors, nuclear factor-k B,
(STAT) factors, STAT4 and T-bet, resulting in the production and activator protein 1, inducing transcription of inflamma-
of effector cytokines, IFN-g, and TNF-a by the differentiated tory cytokines (7). They also effect post-translational events,
Th1 cells. Th1 cells activate macrophages to mount cell- including intracellular signaling and effector cytokine mRNA
mediated immune responses against intracellular pathogens. stability (8). Downstream effects reduce leukocyte trafficking
Th2 differentiation occurs in the presence of IL-4 to activate (by attenuating TNF-a– and IL-1b–enhanced endothelial cell

Figure 1. | Production of major acute innate cytokines involved in local and systemic responses following leukocyte activation via TLRs or
danger-associated molecular pattern receptors. DC, dendritic cell; GM-CSF, granulocyte-macrophage colony–stimulating factor; MC, mast
cell; Rc, receptor; TLR, Toll-like receptor.
Clin J Am Soc Nephrol 10: 2243–2254, December, 2015 Cytokine: Names and Numbers, Holdsworth and Gan 2245

adhesion molecule expression). They reduce the number of

B cell maturation
circulating T cells and inhibit IL-2 production. Th cell differ-

CXCR4, CXCR5
TFH entiation shows a shift to Th2 with attenuation of monocyte
IL-12 without effecting IL-10 production. This results in the
IL-21, IL-6
reduction of Th1 responses favoring Th17 (9). A number of
other well established anti-inflammatory drugs (pentoxifylline

IL-21
Bcl-6
and thalidomide) also attenuate inflammatory cytokine gene
transcription (10).

Skin homeostasis
and pathology
CCR4, CCR6,

Biologic Approaches to Cytokine Therapeutic

TGF-a, IL-6
Th22

Manipulation
CCR10

Attempts to biologically target cytokines were led by stud-

IL-22

ies in shock; however, their beneficial effects were limited.

Arh

Clinical trials in rheumatoid arthritis (RA) and psoriasis were

more effective. These studies in RA and psoriasis were fa-
Tissue inflammation

cilitated by the capacity to repeatedly access the affected

tissues (synovial joints and skin) to determine dominant
IL-9, IL-10, IL-17,

cytokines and to correlate their presence with disease severity,

IL-21, IL-22
STAT6, IRF4,

production
and mucus

outcomes, and treatment responses. Administering immuno-

Th9

TGF-b, IL-4

GATA3

neutralizing candidate cytokines in synovial and dermal

tissues in vitro allows their biologic effect to be studied.
Finally, preclinical study of the biologic effects of admin-
—

istering or blocking cytokines in vivo in relevant animal

models provided proof of concept for efficacy, specificity,
IL-17A–F, IL-21,

and potential toxicities. The clinical success of anti–TNF-a

Autoimmunity
STAT3, RORgt

IL-22, IL-23
CCR4, CCR6

monoclonal antibodies (mAbs) in human RA and psoriasis

TGF-b, IL-6,
Th17

helped establish an accepted role for these biologics as main-

stream therapeutics (11). Subsequently, anti–TNF-a strategies
IL-23

were successfully applied to other related rheumatologic dis-

eases (12) and then to inflammatory bowel disease (IBD) (13).
However, anti–TNF-a therapy was not effective in ANCA
vasculitis (14) and multiple sclerosis (MS) (15). A number of
CCR8, CXCR4

IgE immunity
STAT6, GATA3

IL-4, IL-5, IL-13

Table 1. Phenotypical and functional characteristic profiling of CD41 T helper subsets

different strategies have been used to achieve therapeutic

Humoral and
CCR3, CCR4,

outcomes by cytokine manipulation. Most involve neutraliz-

Th2

ing cytokine effects in disease either by immunoneutralization

or the use of competitive decoy receptors (Table 2). Several
IL-4

potentially therapeutic mAbs targeting other key innate

proinflammatory cytokines (particularly IL-1 and IL-6)
were developed and tested in a number of inflammatory
CXCR3, CCR5

Cell mediated
IFN-g, TNF-a
STAT4, T-bet

and autoimmune diseases.

IL-12, IFN-g

immunity
Th1

Cytokines for Which Biologic Therapies Have Shown

Clinical Effectiveness
TNF-a
Treg, regulatory T cells; TFH, T follicular helper.

There are now five approved therapeutics for rheumato-

CCR7, CXCR4

IL-10, TGF-b,

logic use, including RA, ankylosing spondylitis, and psoriatic

tolerance
Treg

arthritis. Four are mAbs (infliximab, centolizumab, adalimumab,

Immune
IL-35

and golimumab), whereas etanercept is a recombinant human

Foxp3
IL-10

TNF receptor (Rc) fused to the Fc portion of IgG that acts as a

competitive inhibitor. These therapeutics modify inflamma-
tory joint damage and systemic inflammatory symptoms (16).
Cell surface chemokine

Optimal outcomes in RA often require combination of con-

Pathway determining

Transcription factors

ventional methotrexate with anti–TNF-a mAb (17).

Signature cytokines
Characteristic

Effector responses

IL-6
cytokines

IL-6 is a pleiotropic cytokine first described as a T- and B-

receptors

cell growth factor produced by T cells, macrophages, and

endothelial cells. It is a potent inducer of local and systemic
inflammation where it plays a key role in the acute phase
response (e.g., IL-6 binds to cell surface IL-6Rc and
2246 Clinical Journal of the American Society of Nephrology

Th1 (driven by IL-12) and Th17 (enhanced by IL-23) path-

Table 2. Strategies used for therapeutic cytokine manipulation ways of Th differentiation. Ustekinumab and briakinumab
are such inhibitory mAbs. They have been assessed in se-
Monoclonal antibody- IL-1, IL-6, TNF-a, IL-12, vere refractory Crohn’s disease but without efficacy (23).
mediated cytokine IL-23/IL-23, IL-17, Ustekinumab is also effective in psoriasis (24).
immunoneutralization IFN-a
Modified cytokine CTLA-4, TNF-a Rc IL-17A
receptors: competitive IL-17A is important in host defense by mobilizing and
inhibitors
activating neutrophils, whereas pathologic IL-17A responses
Upstream drugs with Syk, S1P, BLyS, JAK
efficacy through lead to the development of autoimmunity. Secukinumb is an
cytokine attenuation inhibitory anti–IL-17A mAb and is effective in psoriasis,
Immunomodulating IL-10, TGF-b psoriatic arthritis, and ankylosing spondylitis (25); however,
cytokines as therapeutic studies in RA show mixed results and no clear consensus of
agents significant benefit (26). Furthermore, in Crohn’s disease treated
Cytokine gene therapy IL-1Ra with secukinumb, no benefit or disease excerbation was
observed (27). In a phase II clinical trial, secukinumab treat-
CTLA-4, cytotoxic T lymphocyte antigen-4; Rc, receptor; Syk, ment showed promising results in MS (28).
spleen tyrosine kinase; BLyS, B lymphocyte stimulator; JAK,
Janus kinase. IL-10
This cytokine can attenuate the production of inflam-
matory cytokines. IL-10 is a prominent participant in human
inflammatory diseases (e.g., significant amounts can be mea-
sured in the synovium of patients with RA). Administration
signaling is facilitated by glycoprotein 130). Tocilizumab of IL-10 did not attenuate RA activity (29), but it is beneficial
is a mAb targeting IL-6Ra. This mAb attenuates joint in- in psoriatic arthritis (30). In ulcerative colitis, IL-10 was in-
flammation, bone erosion, and systemic inflammation in effective when administered at doses that were not associ-
RA (18). Tocilizumab is also effective in juvenile RA (Still’s ated with side effects, including anemia (31).
disease) and Castleman’s disease (19).
Biologic Therapies that Have Downstream
IL-1
IL-1 is an innate cytokine with powerful capacity to Anticytokine Effects
activate macrophages and epithelial cells and acts in con- Cytotoxic T Lymphocyte Antigen-4
While strictly speaking, cytotoxic T lymphocyte antigen-
cert with IL-6 to induce systemic acute phase responses. It
4 (CTLA-4) Ig is not primarily a cytokine therapy, blockade
has a natural antagonist, IL-1RA. IL-1RA competitively
of costimulatory molecules essential to adaptive immunity
inhibits IL-1Rc binding by IL-1a and IL-1b. Anakinra is a
can secondarily block cytokine-mediated inflammation.
human recombinant form of IL-1RA. Therapeutically, anakinra
T-cell surface receptors CD28 and CTLA-4 bind APC
has been unsuccessful compared with anti–TNF-a ther-
ligands CD80 and CD86. CD28 is pivotal in enhancing
apy for RA, but it is highly effective in modulating the
immune activation, whereas CTLA-4 delivers an inhibitory
Cryopyrin-associated periodic syndromes, including neo-
signal. Abatacept and belatecept are approved by the US
natal onset multisystem inflammatory disease, Muckle–
Food and Drug Administration for treatment of resistant RA
Wells syndrome, acute and chronic gout, and juvenile
(32). It is effective in this situation; however, it as expected
RA (20).
carries a risk of serious infection.
IL-2
IL-2 is a growth factor for activated T cells. CD28- Cytokine Gene Therapy
dependent costimulation of activated T cells induces expres- Gene therapy has been demonstrated to be an effective
sion of the high affinity IL-2 (g, b, and d) receptor (CD25). way of treating pathologic inflammation. Rheumatoid syno-
Basiliximab is a mAb designed to bind and block the IL-2Rc via are arthroscopically removed from patients awaiting joint
on activated T cells. This mAb is widely used to prevent replacement and transfected with the gene for IL-1RA.
early kidney transplant rejection. Reimplantation of this transfected synovia back into the
A Cochrane systematic review shows that basiliximab is joint attenuated disease (33). This technique has also been
effective at reducing rejection 3 and 6 months postrenal trans- successfully used in collagen arthritis.
plantation. Because Tregs express high levels of CD25, there is
the potential risk that its efficacy may be limited by its Cytokine Signal Transduction Inhibition
potential effect on blocking immunomodulation. A human- Blocking cytokine signaling pathways can effectively
ized anti–IL-2Rc mAb, daclizumab shows no apparent differ- prevent cytokine participation in inflammatory diseases. A
ences from basiliximab (21) and has been reported to be number of small molecular weight inhibitors have pro-
effective in treating uveitis in eight of ten patients in an gressed to clinical trial; however, specificity and toxicity
open-label study (22). have limited their progress to the clinic.

IL-12/IL-23 Janus Kinase Inhibitors

These dimeric molecules share one chain in common, Janus kinase (JAK) inhibitors are small molecules with
p40. Targeting p40 offers the opportunity to attenuate both multiple effects on cytokine signaling pathways that inhibit
Clin J Am Soc Nephrol 10: 2243–2254, December, 2015 Cytokine: Names and Numbers, Holdsworth and Gan 2247

the effects of cytokine-induced cell activation and conse- clinical data available do not support this role in human
quent pathologic inflammation (34). Tofacitinib preferen- RA and IBD. However, preliminary data in MS, targeting
tially inhibits JAK-1 and JAK-3. In clinical trials, the degree IL-17, shows evidence of benefit. Although much more data
of benefit in resistant RA was similar in efficacy to are necessary before firm conclusions can be drawn, these
adalimumab, a TNF-a inhibitor. It may lack specificity be- observations on the therapeutic benefit on inhibiting single
cause side effects, including sepsis, disturbed liver func- cytokines suggest that different combinations of cytokine
tion tests, raised creatinine, and neutropenia, were may direct specific patterns of disease (Table 3).
reported during its use (35).

Spleen Kinase Inhibitors Therapeutic Cytokine Targeting in Renal Diseases

Inhibition of spleen kinase signal transduction pathway There are three renal diseases where there is good
prevents downstream gene transcription (i.e., synthesis of evidence that immune cytokines play significant roles in
proinflammatory cytokines). The best studied spleen ki- disease pathogenesis and where their therapeutic manip-
nase inhibitor is fostamatinib. It has been successfully ulation could potentially be efficacious. These diseases are
used in collagen arthritis in mice (36) and has been studied AKI, lupus nephritis, and proliferative/crescentic GN.
in .3000 patients with RA in several clinical trials. Re-
sponder rates for acute disease were encouraging, but Innate Immunity: AKI
side effects were common (37). Fostamatinib acts by in- AKI is the most common hospital-based kidney disease
hibiting TNF-a–induced IL-6 production by fibroblast-like (37). Much of our understanding of the mechanisms of in-
synoviocytes (38). jury in AKI come from two experimental models: ischemia
Collectively, data from current clinical trials are insuf- reperfusion injury (IRI) and cisplatin-induced AKI. These
ficient to draw general statements about cytokine thera- models highlight the roles of cytokines and leukocytes in
peutic manipulation in chronic autoimmune inflammatory mediating injury. This is sterile inflammation. The initiat-
disease in humans. However, several observations seem ing trigger is followed by tissue stress and necrosis, initi-
appropriate. TNF-a is clearly an important mediator in in- ating the production of pathogen-associated molecular
jurious inflammation in several autoimmune and autoin- pattern molecules (including hypoxia-inducible factor
flammatory diseases. However, there is also evidence to and high-mobility group box 1), inducing the upregulation
suggest that in other diseases, it is either redundant or of leukocyte adhesion molecules, chemokines, and TLR
potentially immunomodulatory (MS and ANCA vasculi- signaling (39). Leukocyte infiltration is rapid and signifi-
tis). IL-1b is also strongly linked to most autoinflammatory cant, involving neutrophils, monocyte, macrophages,
diseases and gout. Clinical trials with IL-6 are more lim- and a variety of T cells (including CD41 Th1 cells, natural
ited, it is present together with TNF-a (in RA) and both killer cells, NKT cells, gd T cells, and DCs) (40).
TNF-a and IL-1b in autoinflammatory diseases. The fact Macrophages, DCs, and MCs are potent producers of
that individual immunoneutralization of IL-6 is beneficial TNF-a, whereas MCs are the only leukocytes that store
in these diseases suggests independent requirement for the presynthesized TNF-a in granules. Blocking degranulation
expression of this cytokine. The effectiveness of IL-17 and of MCs in cisplatin AKI with disodium cromoglycate pre-
IL-23 immunoneutralization to attenuate psoriasis and vented the increase of TNF-a in serum and protected from
psoriatic arthritis supports the case for these diseases being injury (41). Inhibition of TNF-a is also beneficial in endotoxin-,
Th17 mediated. However, TNF-a is also required for the cisplatin-, and ischemia-induced AKI (42,43). IL-1 is respon-
generation of inflammation in this disease because TNF-a sible for enhancing neutrophil influx in IRI (44). NLRP3
neutralization is also beneficial. Although experimental ani- inflammasome knockout (2/2) mice are protected against
mal models have provided evidence that the CD41 Th17 IRI but not in cisplatin-induced AKI (45). However,
subset directs inflammatory injury in RA and IBD, the caspase-12/2 mice are protected from cisplatin-induced

Table 3. Clinical efficacy of biological inhibitors of cytokines

Cytokine Inhibition Biologic Effectiveness Proven Ineffective

IL-1 Anakinra Juvenile arthritis and cryopyrin-associated RA

Canakinumab periodic syndromes
Rilonacept
IL-6 Tocilizumab RA and juvenile arthritis —
TNF-a Adalimumab RA, juvenile arthritis, ankylosing Multiple sclerosis and
Certolizumab spondylitis, IBD, and psoriasis ANCA vasculitis
Etanercept
Golimumab
Infliximab
IL-12/IL-23 Ustekinumab Ankylosing spondylitis, IBD, and psoriasis —
Briakinumab
IL-17 Secukinumab Ankylosing spondylitis and psoriasis RA and IBD

RA, rheumatoid arthritis; IBD, inflammatory bowel disease.

2248 Clinical Journal of the American Society of Nephrology

AKI (46), but IL-1b2/2 mice are not (47). The role of IL-6 in the IFN-a signature (57). The levels of serum IFN-a and
AKI is complex. Evidence in ischemic AKI is consistent with expression of IFN-a–regulated genes correlate with disease
an injurious role for an endogenous IL-6 (48). However in an activity, autoantibodies, and complement levels (58). IFN-a
HgCl2 model, it was shown that while IL-6–mediated inflam- signaling pathway polymorphisms have been shown in fam-
matory responses contributed to injury, IL-6 trans-signaling ilies with SLE (59). IFN-a is thought to be a promising ther-
induced protective responses (49). apeutic target for SLE, and several mAb inhibitors are in
Cytokine-based immunomodulation can potentially be clinical trials. Sifalimumab is a humanized anti–IFN-a
used as preventative or therapeutic in AKI. The therapeutic mAb. Its use in SLE was associated with reduction in SLE
potential of administering anti-inflammatory cytokine IL-10 flares and activity (60). In a recent clinical trial, use of
has been demonstrated to be effective in both ischemic and rontalizumab (another anti–IFN-a mAb) reduced the expres-
cisplatin-induced AKI (50). More recently, it has been appre- sion patterns of IFN-a–driven genes, improved disease se-
ciated that Tregs can protect from cisplatin (51) and ischemic verity, and improved flare rates in patients with SLE.
AKI (52). Adoptive transfer of Tregs before cisplatin and However, patients with lupus nephritis were not included
before ischemia protected from the development of AKI. in this trial. AGS-009 is an IgG4 humanized mAb that in-
The number of Tregs required for protection in mice sug- duced significant attenuation of IFN-a signatures after a
gests the procedure is feasible in humans. Additionally, single dose (61). A novel approach has been to vaccinate
transferring Tregs to mice 24 hours after ischemic AKI was patients with SLE with IFN-a–kinoid molecules to induce
beneficial in promoting repair (53). autoantibodies to IFN-a. All immunized patients returned
Cytokines released from kidneys with AKI can have the IFN-a signature to baseline (62).
significant effects on distal organs by circulatory spillover. TNF-a. Mouse models of lupus nephritis have shown
Mortality in intensive care units is predicted by distal both potentially protective and accentuating roles for TNF-a.
organ involvement in AKI. Recent studies suggest systemic New Zealand Black (NZB)/New Zealand White (NZW) and
proinflammatory effects are triggered in three waves by the MRL/lpr mice with decreased synthetic capacity of TNF-a
immune release of host alarm signals (alarmins) from the develop lupus nephritis, but in the kidney, intrarenal ex-
AKI-damaged kidney (54). This begins with a uric acid surge, pression of TNF-a correlates with disease activity and in-
which induces a second wave of endothelial cell Weibel– flammation (63). In NZB/NZW mice with IFN-a–induced
Palade bodies released, which is then followed by a third nephritis, anti–TNF-a antibodies attenuate renal inflam-
wave of high-mobility group box 1 protein release. These mation and injury despite maintained immune complex
events are potent triggers for GM-CSF, IFN-g, CXCL8, deposition (64).
G-CSF, IL-12, TNF-a, and IL-6 (55). Recently, renal DCs The data on the role of TNF-a is conflicting; hence, the
were implicated in inducing cytokine-mediated injury in benefits of targeting TNF-a in human lupus nephritis is un-
ischemic AKI. Renal DCs can powerfully influence AKI by certain. However, there is the general view that there is suf-
enhancing or attenuating injury. After injury, DCs initiate ficient data to advise against TNF-a inhibition. Several studies
innate inflammatory responses presenting glycolipids and show that circulating levels of TNF-a and renal expression is
stimulating NKT cells, recruiting neutrophils and initiating increased (65); however, other studies show TNF-a produc-
the IL-17/IL-23 signaling pathway. DCs produce TNF-a, tion by PBMCs was lower in patients with lupus nephritis
IL-6, IL-12, IL-23, IL-17, and IFN-g to amplify injury and than controls (66). Additionally, TNF-a production was as-
inflammation. However, adenosine A2ARc signaling can sociated with reduced TNF-a bioactivity because of high
attenuate DC activation and protect from injury in ischemic serum levels of TNF receptors, which also correlated with
AKI (56). increased disease activity (67). Finally, in patients with lupus
nephritis, 10 weeks of infliximab treatment reduced protein-
Autoimmune Crescentic Glomerulonephritis uria but increased anti-DNA antibodies. Longer treatment
Lupus Nephritis was associated with adverse effects (68). In patients with
SLE is a disease with evidence of genetic, epigenetic, and RA treated with anti–TNF-a mAbs, lupus syndromes devel-
environmental contributions. There appears to be many oped, anti-DNAs were induced (69), and some patients
different immune abnormalities associated with this dis- developed GN (70).
ease, including significant abnormalities of cytokine circuits. IL-6. IL-6 is likely to act in concert with type 1 IFNs to
It is also likely that there are multiple paths of autoimmunity induce B-cell autoimmunity in SLE. Its levels are elevated
depending in part on which component of immunomodu- in lupus nephritis and correlate with disease activity (71).
lation is defective. Although it is likely that cytokines are IL-6 has been demonstrated in glomerular immune com-
therapeutic targets in this disease, the known presence of plexes and proximal tubular epithelial cells in lupus ne-
multiple immunoregulatory abnormalities suggests that SLE phritis (72). Intrinsic renal cells produce IL-6, and this can
should not be considered as a single homogenous disease. be enhanced by anti-DNA antibodies (73). In lupus-prone
IFN-a. There is good evidence that IFN-a is an impor- mice, IL-6 exacerbates GN while inhibiting IL-6 signaling
tant inducer of antichromatin autoimmunity in patients attenuated GN and reducing autoimmunity, therefore en-
developing SLE. Early in the disease, it has been demon- hancing survival (74). Most IL-6 inhibition trials have oc-
strated that immune complexes (containing DNA and/or curred in RA while data are emerging in SLE. Tocilizumab
RNA) are taken up by plasmacytoid DCs by FCgR-mediated reduced acute phase reactants, anti–double-stranded DNA
internalization. Together with TLR7 and TLR9 stimulation, antibody, and SELENA-SLEDAI scores in patients with
this induces IFN-a production, driving autoimmunity. moderately active lupus nephritis (75).
Evidence supporting this comes from the high incidence A number of biologic interventions target molecules or
of IFN-a–regulated genes in PBMCs of patients with SLE, immune cells upstream of cytokine production. The beneficial
Clin J Am Soc Nephrol 10: 2243–2254, December, 2015 Cytokine: Names and Numbers, Holdsworth and Gan 2249

effects are likely to result from their effects on cytokine animal model of human crescentic GN. There is considerable
mediation of target organ inflammation. data showing that immune cytokines are critically involved
B-cell Activating Factor. B-cell activating factor is also in inducing nephritogenic autoimmunity and mediating glo-
known as B lymphocyte stimulator and is essential for B-cell merular injury in these models. Moreover, studies in this
maturation, survival, and Ig class switching. Its levels are model provide proof of concept that the inhibition of selected
elevated in SLE and correlate with disease activity and flares cytokines can prevent and treat disease.
(76). Belimumab, a humanized anti-B lymphocyte stimulator Numerous innate cytokines have been associated with
mAb has been shown in two trials to demonstrate a modest pathogenesis of anti-GBM GN. A pathogenic role in anti-
but significant benefit in reducing disease activity. Patients GBM GN has been demonstrated for each of the following
with lupus nephritis were excluded, but in one trial, 15% of innate cytokines: GM-CSF, G-CSF, IL-1b, TNF-a, and
patients had evidence of nephritis. A post hoc analysis CXCL8, by studies in cytokine gene–deleted mice. All of
showed significant reduction in proteinuria. Trials in lupus these innate cytokines recruit inflammatory cells to the
nephritis are underway (77,78). kidney and direct the subsequent development of anti-
Abatacept. The data at hand do not provide evidence for GBM GN. Gene deletion of the key Th1 cytokines (IL-12
CTLA4-Ig efficacy in the treatment of lupus nephritis. A and IFN-g) resulted in attenuated crescentic GN, and gene
phase IIb trial involving patients with lupus with poly- deletion of the key Th1 transcription factor (T-bet) is pro-
arthritis and discoid lupus did not meet its primary or tective (85,86). After the discovery of the CD41 Th17 subset,
secondary end point, flare prevention, and the infection studies using mice deficient in p19, p35, and p40 (compo-
incidence was significantly higher in the abatacept arm nents of the key Th1 and Th17 cytokines, IL-12 and IL-23,
(79). In another 12-month trial of abatacept or placebo, intra- respectively) were used to analyze the relative contributions
venous infusion plus steroid and mycophenolate mofetil of each Th subset in anti-GBM GN. Paust et al. demonstrated
were compared in patients with class III and class IV lupus that Th17 cells contributes to anti-GBM GN with the use of
nephritis. Complete response and renal improvement crite- IL-23p192/2 and IL-17A2/2 mice (87), whereas Odobasic
ria were the same in all groups. Infection was not higher in et al. examined the reciprocal relationship between Th1 and
the abatacept group (80). Th17 and demonstrated that early nephritogenic responses
Anti–TNF-Related Weak Inducer of Apoptosis. There were mediated by Th17 cells, but late disease is Th1 depen-
is growing evidence for the anti–TNF-related weak inducer dent. They also demonstrated that each Th subset counter-
of apoptosis (Tweak)/factor inducible 14 pathway in en- regulated the other (88). Furthermore, Steinmetz et al. used
hancing injury in lupus nephritis. In lupus nephritis, mice with gene deletion of RORg-t, the key Th17 transcrip-
Tweak and its receptor are upregulated in renal tubular tion factor, to confirm the participation of the CD41 Th17
cells, inducing proinflammatory cytokines, including IL-6, subset (89). Direct comparison has been made between the
adhesion molecules, and chemokines (81). Immunoneu- effects of transferring Th17 and Th1 polarized ovalbumin
tralization of Tweak decreases renal inflammation in mu- (OVA) specific CD41 TCR transgenic cells into naïve mice
rine models (82), and these mAb are being studied in lupus with OVA planted on the GBM using a non-nephritogenic
nephritis (ClinicalTrials.gov identifier: NCT0130890). anti-GBM/OVA conjugated antibody. Transfer of both CD41
Laquinimod. Laquinimod is a small molecule that im- T-cell clones induced GN. However, transfer of Th1-polarized
munomodulates APCs to redirect Th subset differentia- cells induced a monocyte and macrophage predominant in-
tion with downregulation of IL-6, IL-12, IL-23, IL-17, and filtrate lesion, whereas Th17-polarized cells induced less in-
TNF-a and increased IL-10. In experimental murine lupus, jury with a neutrophil predominant infiltrate (90). To assess
laquinimod delayed the onset of lupus nephritis. When key Th2 cytokines, anti-GBM GN was induced in IL-42/2
administered as a therapeutic, it attenuated disease severity and IL-102/2 mice. Both groups had augmented Th1 re-
by reducing IFN-g and IL-17A production by splenocytes sponses and increased glomerular injury, whereas infusion
while enhancing IL-10 and Treg frequency (83). In a phase of IL-10 attenuated disease. Tregs are not only important in
II study in active lupus nephritis, mycophenolate mofetil maintaining self-tolerance but are also necessary in control-
and high-dose steroid were administered with or without ling overt inflammatory responses. Transfer of Tregs (CD41
laquinimod. Laquinimod had an additive effect with renal CD251) before and after the induction of experimental anti-
function and proteinuria improvement. Adverse effects were GBM GN suppressed the development of GN by reducing
not observed (84). Th1 responses (91). Interestingly, Eller et al. demonstrated
Despite many trials of therapeutics that attenuate cyto- that Treg-derived IL-9 is essential for the recruitment of
kine action being performed in SLE, there is still much that MCs, and both are required to attenuate anti-GBM GN (92).
needs to be understood about the role of cytokines in this Cytokine Production by Resident Renal Cells. Resident
disease. Unfortunately, the simple application of therapies cells within the kidney, including tubular and glomerular
successful in other immune inflammatory diseases (as in cells, interact with infiltrating leukocytes resulting in their
the case of anti–TNF-a immune neutralization) appears to synthesis of injurious TNF-a in response to leukocyte-
be much more problematic in SLE. Finally, the diversity of produced IL-1 (73). The relative roles of leukocyte and
patterns of disease and the involvement of different organs resident cytokine production have been studied in anti-
means lupus nephritis is unfortunately an exclusion in GBM GN in mice using cytokine chimeric mice where the
many trials, denying these patients the opportunity for cytokine gene has been deleted from either bone marrow–
potentially more effective treatments. derived leukocytes or from resident renal cells (86). Nonchi-
Experimental Antiglomerular Basement Membrane meric TNF-a2/2 mice are significantly protected from the
Glomerulonephritis. Experimental antiglomerular base- development of GN. When the TNF-a gene is knocked out
ment membrane (GBM) GN is the most widely studied from resident cells, similar attenuation was observed,
2250 Clinical Journal of the American Society of Nephrology

whereas knockout of the TNF-a gene in bone marrow only target autoantigens, proteinase 3 or myeloperoxidase
caused mild protection, suggesting that TNF-a produced by (MPO) (93). In treatment of refractory disease with T
resident cells is the major source of injurious TNF-a in this cell–specific targeted therapies, antithymocyte globulin
disease. These studies also produced evidence of complex was beneficial and capable of inducing remission (94). Fur-
cytokine interactions between resident cells and infiltrating thermore, cytokine profiling of biopsied nasal mucosal tis-
leukocytes. Studies with IL-1b2/2 and IL-1R12/2 mice sue, bronchoalveolar lavage, and PBMCs from patients
showed that IL-1b mainly derived from leukocytes actives with granulomatous polyangiitis demonstrated increased
IL-1R1 on resident cells, inducing TNF-a production that expression of IFN-g, denoting a Th1 cytokine pattern (95).
causes significant glomerular injury (86) (Figure 2). Nogueira et al. found that in the serum of acute or convales-
Autoimmune Anti-GBM Glomerulonephritis. In auto- cent AAV patients, IL-17A and IL-23 levels were increased,
immune anti-GBM GN, the target autoantigen is the non- and this correlated with disease severity and ANCA titer
collagenase domain of the alpha 3 chain of type IV collagen. (96). IL-6 was also elevated in active disease. Chavele et al.
Immunization with this antigen induces autoimmunity shown reported that in patients with MPO-AAV, MPO-stimulated
by the production of circulating anti-GBM antibodies and the recall responses showed elevated IFN-g (97). Collectively,
development of crescentic GN. IFN-g2/2 mice developed these data provide evidence in support of both Th1 and
worse disease. The relative contributions of Th1 and Th17 Th17 involvement in AAV. Furthermore, IL-17–producing
to disease development were assessed using p352/2 (defi- cells were found in renal biopsies from patients with acute
cient in Th1 subset) and p192/2 (deficient in Th17 subset) vasculitis, and most of the IL-17–positive cells present were
mice. The p192/2 mice were protected from GN, but the innate leukocytes (neutrophils and MCs) (98).
p352/2 mice were unaffected compared with controls, In experimental MPO-ANCA GN, IL-17A2/2 mice
confirming a pathogenic role for Th17 but not for Th1 in were protected from the development of anti-MPO auto-
this disease. immunity and glomerular injury (99). Immunoneutraliza-
ANCA-Associated Crescentic Glomerulonephritis. The tion of TNF-a caused significant reduction in lung
most common cause of crescentic GN is ANCA-associated hemorrhage and renal injury in Wistar–Kyoto rats with
vasculitis (AAV). Evidence suggests cytokines directing induced anti-MPO AAV (100).
the underlying nephritogenic autoimmunity are likely to The only cytokine-based clinical trials in AAV have been
be therapeutic targets that could be neutralized with avail- of anti–TNF-a. Treatment with etanercept (anti–TNF-a
able biologic agents. mAb) was not effective and was associated with a high
PBMCs from patients with ANCA-associated GN have rate of treatment-related adverse side effects (101). A
CD41 T cells that proliferate when stimulated with the smaller clinical trial using adalimumab with prednisolone

Figure 2. | Innate macrophages produce IL-1 which binds to IL-1Rc on intrinsic renal cells (endothelial cells, podocytes, and mesangial cells)
to produce injurious TNF-a that amplifies T effector cell responses resulting in crescent formation and glomerular injury. Rc, receptor.
Clin J Am Soc Nephrol 10: 2243–2254, December, 2015 Cytokine: Names and Numbers, Holdsworth and Gan 2251

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