Lysophosphatidic acid (LPA)

Lipidomics Gateway (28 October 2009) [doi:10.1038/lipidmaps.2009.31]

One of the most active of the bioactive phospholipids, LPA is soluble in both cell membranes and in aqueous fluid, and
acts in many cell signaling pathways.
Structure of LPA with a saturated acyl chain in the sn1 position (top) or an unsaturated acyl chain in the sn2 position
(bottom). Image created using the LIPID MAPS glycerophospholipid structure drawing tool. For nomenclature
information, visit Author Tools.
The bulk of LPA production occurs in bodily fluids, outside the cell. From there, it can bind to, and activate, upwards
of six different cell surface receptors, initiating a diverse range of signaling cascades. LPA also has unclearly defined
intracellular roles, and activates at least one nuclear receptor. Besides these direct interactions, the regulated
presence of LPA in the membrane can induce curvature, and is involved in membrane transport processes.
LPA: Composition, production and destruction
As the name suggests, LPA is identical in structure to phosphatidic acid (PA), except that LPA has a single acyl chain.
LPA can be directly generated from PA, through the action of phospholipase A-type enzymes, but in the main pathway
of production the choline headgroup from lysophosphatidylcholine (LPC) is removed by the secreted enzyme autotaxin
1
. Circulating LPA is rapidly turned over by lipid phosphate phosphatases (LPPs), which terminate its signal by
dephosphorylation 2 . The LPP superfamily includes three LPP enzymes and a number of related proteins that are
thought to possess LPP activity. However, recent data suggests that a brain-specific family member modulates LPA
signaling at excitatory synapses by simply binding, not hydrolyzing, the phospholipid, thus preventing its interaction
with a receptor 3 .
Signaling: Tailored reception
The functions of LPA are extensive and include roles in development, but individual cellular responses vary widely.
Specific effects are determined by the local concentration of LPA, and on the receptors expressed by a cell. Five G-
protein-coupled receptors (GPCRs) have been identified as specific for LPA (designated LPA 1–5), and a further three
candidates await full validation 4 . One of these, P2Y5, was identified as essential for the maintenance of human hair
growth 5 , and was recently reported to reduce intestinal cell adhesion 6 . In common with other LPA receptors, P2Y5
can transactivate the epidermal growth factor receptor 6 , introducing a further layer of complexity to LPA-mediated
signaling.
Most reported cellular responses to LPA have been attributed to cell surface GPCR activation, but it can also bind the
nuclear peroxisome proliferator-activated receptor gamma (PPARγ), and initiate early stages of atherosclerosis 7 . A
few other intracellular targets have been reported, including LPA 1, which appears to be trafficked to the nucleus in
response to extracellular LPA 8 . Furthermore, our article this month “Lipid signaling: LPA's ways of actin” highlights
another potential intracellular activity of LPA as it binds to and inhibits the actin-modifying protein villin 9 .
Membrane transport: Curves required
A further way in which LPA can modulate cell behavior is by altering membrane dynamics. LPA acyltransferase (LPAAT)
enzymes condense LPA and fatty acyl-coenzyme A to produce PA. The LPA used can be taken from either the
membrane or cytosolic pool, with profound consequences for membrane architecture as both LPA and PA promote
curvature, but in opposite directions 10 . Recently, we highlighted the role of a novel LPAAT in Golgi transport function
(See “Lipids and Golgi function: An acyltransferase stops traffic”) 11 .
Detection: Diseases, species and identity crises
With so many physiological responses to LPA, there is great potential for things to go wrong. Aberrant LPA signaling is
implicated in numerous pathologies, including cancer and heart disease 12 b13 , and the pathways involved are potential
therapeutic targets. To counteract specific functions of LPA, there is a need to define the roles of distinct molecular
species in different tissues and developmental stages. It is also unclear how the intra and extracellular functions of
LPA are related. Modern lipidomics techniques, as for phosphatidylcholine, are increasingly capable of answering these
questions. For example, the work highlighted this month in “Brain lipids: Male mice show their age” found that levels
of LPA increase with age in the brains of male, but not female, mice 14 .
These techniques, however, are still being refined; a recent study by Zhao & Xu suggests that for quantification of LPA
using a favored lipidomics approach (electrospray ionization coupled with tandem mass spectrometry, ESI–MS/MS), it is
first necessary to separate LPA from any LPC in the sample, because a proportion of LPC loses its choline headgroup at
the ionization source and can generate a false LPA signal 15
LPA induces osteoblast differentiation through interplay of two receptors: LPA1 and LPA4
Abstract
The bioactive phospholipid, lysophosphatidic acid (LPA), acting through at least five distinct receptors LPA1–LPA5,
plays important roles in numerous biological processes. Here we report that LPA induces osteoblastic differentiation of
human mesenchymal stem cells hMSC-TERT. We find that hMSC-TERT mostly express two LPA receptors, LPA1 and
LPA4, and undergo osteoblastic differentiation in serum-containing medium. Inhibition of LPA1 with Ki16425
completely abrogates osteogenesis, indicating that this process is mediated by LPA in the serum through activation of
LPA1. In contrast to LPA1, down-regulation of LPA4 expression with shRNA significantly increases osteogenesis,
suggesting that this receptor normally exerts negative effects on differentiation. Mechanistically, we find that in
hMSC-TERT, LPA induces a rise in both cAMP and Ca 2+. The rise in Ca2+ is completely abolished by Ki16425, whereas
LPA-mediated cAMP increase is not sensitive to Ki16425. To test if LPA signaling pathways controlling osteogenesis in
vitro translate into animal physiology, we evaluated the bones of LPA4-deficient mice. Consistent with the ability of
LPA4 to inhibit osteoblastic differentiation of stem cells, LPA4-deficient mice have increased trabecular bone volume,
number, and thickness. J. Cell. Biochem. 109: 794–800, 2010. © 2010 Wiley-Liss, Inc.
Interleukin 6 mediates the lysophosphatidic acid-regulated cross-talk between stromal and epithelial prostate
cancer cells.
by Perumal Sivashanmugam, Linda Tang, Yehia Daaka
Abstract
The interaction between stromal and epithelial cells is critical for the initiation and progression of prostate cancer,
but the molecular determinants responsible for the cross-talk between these two cell types remain largely unknown.
Here, we used a co-culture cell assay to identify messengers involved in the cross-talk between human prostate
stromal PS30 and epithelial LNCaP cells. Stimulation with lysophosphatidic acid (LPA) activates the mitogenic ERK
signaling pathway in PS30, but not LNCaP, cells. The co-culture of PS30 and LNCaP cells results in the activation of ERK
in LNCaP cells and that is further increased in response to stimulation with LPA. Physiologic relevance of the
interaction between PS30 and LNCaP cells is demonstrated using LNCaP xenograft tumor assays. Animals implanted
with a mixture of both cell types develop larger tumors with higher frequency compared with those injected with
LNCaP cells alone. Conditioned medium transfer experiments reveal the PS30-derived inducing factor is soluble and
promotes mitogenic ERK and STAT3 signaling pathways in LNCaP cells. Protein analysis demonstrates that treatment of
the PS30 cells with LPA induces synthesis of interleukin 6 (IL-6). Antibody neutralization experiments reveal that IL-6 is
responsible for the LPA-induced mitogenic signaling and growth of the LNCaP cells. Our findings reveal that the LPA-
regulated secretion of IL-6 is an important messenger linking stromal and epithelial prostate cells, which may be
exploited for the effective treatment of patients with advanced prostate cancer.
The structure and functions of human lysophosphatidic acid acyltransferases. Leung D.W.
Lysophosphatidic acid (LPA) and phosphatidic acid (PA) are two phospholipids involved in signal transduction and in
lipid biosynthesis in cells. LPA acyltransferase (LPAAT), also known as 1-acyl sn-glycerol-3-phosphate acyltransferase
(1-AGPAT) (EC 2.3.1.51), catalyzes the conversion of LPA to PA. Two human isoforms of LPAAT, designated as LPAAT-
alpha (AGPAT1) and LPAAT-beta (AGPAT2), have been extensively characterized. These two proteins contain extensive
sequence similarities to microbial, plant and animal LPAAT sequences. LPAAT-alpha mRNA is uniformly expressed
throughout most tissues with the highest level found in skeletal muscle; whereas LPAAT-beta is differentially
expressed, with the highest level found in heart and liver, and negligible level in brain and placenta. The LPAAT-alpha
gene is located on chromosome 6p21.3, an area within the class III region of the major hiscompatibility complex (MHC)
and the LPAAT-beta gene is mapped to chromosome 9q34.3. Enhanced transcription of LPAAT-beta is suggested for
neoplasm of the female genital tract. Additionally, ectopic LPAAT expression in certain cytokine-responsive cell lines
can effect amplification of cellular signaling processes, such as those leading to enhancement of synthesis of tumor
necrosis factor-alpha and interleukin-6 from cells following stimulation with interleukin-1beta; this suggests that the
LPAAT genes represent candidates for affecting the development of certain cancers or inflammation-associated
diseases.

Signal transduction system for interleukin-6 synthesis stimulated by lipopolysaccharide in human osteoblasts.
Kondo A, Koshihara Y, Togari A.
Source
Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, Nagoya 464-8650, Japan.
Abstract
Lipopolysaccharide (LPS) is a bacterial cell component that plays multifunctional roles in inflammatory reactions, and
one of the roles is as a powerful stimulator of bone resorption. LPS stimulated bone resorption via CD14 in mouse
calvaria and was reported to function as a receptor for bacterial LPS complexed with serum proteins. Interleukin-6 (IL-
6) is capable of stimulating the differentiation of osteoclasts from their hematopoietic precursors, and LPS elevates IL-
6 synthesis in human osteoblastic cells. However, the signaling pathway of LPS-induced IL-6 synthesis in osteoblasts is
unknown. In the present study, we could detect the existence of CD14 in human osteoblastic cells by RT-PCR analysis
and show that LPS increased IL-6 mRNA and synthesis via CD14 in human osteoblastic cells. In human osteoblasts (SaM-
1 cells) treated with 10 microg/ml LPS, increases in IL-6 mRNA and synthesis were inhibited by anti-CD14 antibody
(MEM-18), PD98059 (an inhibitor of classic mitogen-activated protein kinase [MAPK]), or SB203580 (an inhibitor of p38
MAPK) but were not inhibited by H-89 (an inhibitor of protein kinase A [PKA]) and calphostin C (an inhibitor of protein
kinase C [PKC]). Furthermore, LPS-induced IL-6 synthesis was inhibited by curcumin (an inhibitor of activating protein-
1 [AP-1]) but not by pyrrolidine dithiocarbamate (PDTC) (an inhibitor of nuclear factor kappa B [NF-kappaB]). The
findings of the present study suggest that the LPS receptor CD14, existent in human osteoblastic cells, and IL-6
synthesis in response to LPS probably occur via CD14, p38 MAPK, and MAP kinase/extracellular-regulated kinase kinase
(MEK), leading to the transcriptional activation of AP-1 in human osteoblastic cells.

ATP-stimulated interleukin-6 synthesis through P2Y receptors on human osteoblasts.

Ihara H, Hirukawa K, Goto S, Togari A.
Source
Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, Nagoya 464-8650, Japan.
Abstract
We investigated the effect of extracellular adenosine triphosphate (ATP) on the production of interleukin (IL)-6, whose
molecules are capable of stimulating the development of osteoclasts from their hematopoietic precursors as well as
are involved in signal transduction systems in human osteoblastic SaM-1 cells. These human osteoblasts constitutively
expressed P2X4, P2X5, P2X6, P2Y2, P2Y5, and P2Y6 purinergic receptors. ATP increased gene- and protein-expression
of IL-6 in SaM-1 cells. The expression of the IL-6 mRNA was maximal at 1h, and the increase in IL-6 synthesis in
response to ATP (10-100 microM) occurred in a concentration-dependent manner. Over the same concentration range
of the nucleotide that was effective for IL-6 synthesis, ATP caused an increase in the intracellular Ca(2+)
concentration ([Ca(2+)](i)), which increase was inhibited by pretreatment with suramin, a P2Y receptor antagonist, or
2-aminoethoxydiphenyl borate (2-APB), an inositol 1,4,5-trisphosphate receptor blocker, but not by the extracellular
Ca(2+)-chelating agent EGTA. The pretreatment of SaM-1 cells with suramin or 2-APB also inhibited the increase in IL-6
synthesis in response to ATP. These findings suggest that extracellular ATP-induced IL-6 synthesis occurs through P2Y
receptors and mobilization of Ca(2+) from internal stores in human osteoblastic cells.
LPA induces osteoblast differentiation through interplay of two receptors: LPA1 and LPA4.
Liu YB, Kharode Y, Bodine PV, Yaworsky PJ, Robinson JA, Billiard J.
Source
Tissue Repair, Pfizer, Inc., Collegeville, Pennsylvania 19426, USA.
Abstract
The bioactive phospholipid, lysophosphatidic acid (LPA), acting through at least five distinct receptors LPA1-LPA5,
plays important roles in numerous biological processes. Here we report that LPA induces osteoblastic differentiation of
human mesenchymal stem cells hMSC-TERT. We find that hMSC-TERT mostly express two LPA receptors, LPA1 and
LPA4, and undergo osteoblastic differentiation in serum-containing medium. Inhibition of LPA1 with Ki16425
completely abrogates osteogenesis, indicating that this process is mediated by LPA in the serum through activation of
LPA1. In contrast to LPA1, down-regulation of LPA4 expression with shRNA significantly increases osteogenesis,
suggesting that this receptor normally exerts negative effects on differentiation. Mechanistically, we find that in
hMSC-TERT, LPA induces a rise in both cAMP and Ca(2+). The rise in Ca(2+) is completely abolished by Ki16425,
whereas LPA-mediated cAMP increase is not sensitive to Ki16425. To test if LPA signaling pathways controlling
osteogenesis in vitro translate into animal physiology, we evaluated the bones of LPA4-deficient mice. Consistent with
the ability of LPA4 to inhibit osteoblastic differentiation of stem cells, LPA4-deficient mice have increased trabecular
bone volume, number, and thickness.
Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers.
Xu Y, Shen Z, Wiper DW, Wu M, Morton RE, Elson P, Kennedy AW, Belinson J, Markman M, Casey G.
Source
Department of Gynecology and Obstetrics, Cancer Center, Cleveland Clinic Foundation, Ohio 44195, USA.
Abstract
CONTEXT:
Lysophosphatidic acid (LPA) has been shown to stimulate proliferation of ovarian cancer cells and is present in the
ascitic fluid of patients with ovarian cancer.
OBJECTIVES:
To determine whether elevated levels of LPA are present in plasma from patients with ovarian cancer and other
gynecologic malignancies compared with healthy controls and to evaluate whether an elevated LPA plasma level may
be a biomarker for these diseases.
DESIGN:
A research assay was used to measure total LPA levels in plasma from healthy women and women with different
diseases. All LPA assays and comparison of LPA levels and CA125 (an ovarian cancer biomarker) levels were performed
by observers blinded to patient status or group.
SETTING:
The Cleveland Clinic Foundation.
PARTICIPANTS:
A convenience sample of 48 healthy control women, 48 women with ovarian cancer, 36 women with other gynecologic
cancers, 17 women with benign gynecologic diseases, 11 women with breast cancer, and 5 women with leukemias.
MAIN OUTCOME MEASURES:
Total LPA levels in plasma samples from patients and controls.
RESULTS:
Patients in the ovarian cancer group had significantly higher plasma LPA levels (mean, 8.6 micromol/L; range, 1.0-43.1
micromol/L) compared with the healthy control group (mean, 0.6 micromol/L; range, <0.1-6.3 micromol/L) (P<.001).
Elevated plasma LPA levels were detected in 9 of 10 patients with stage I ovarian cancer, 24 of 24 patients with stage
II, III, and IV ovarian cancer, and 14 of 14 patients with recurrent ovarian cancer. Of 36 patients with other
gynecologic cancers, 33 also showed higher LPA levels(mean, 14.9 micromol/L; range, <0.1-63.2 pmol/L), compared
with healthy controls (P<.001). Elevated plasma LPA levels were detected in 5 of 48 controls and 4 of 17 patients with
benign gynecologic diseases and in no women with breast cancer or leukemia. In comparison, among a subset of
patients with ovarian cancer, 28 of 47 had elevated CA125 levels, including 2 of 9 patients with stage I disease.
CONCLUSIONS:
Plasma LPA levels may represent a potential biomarker for ovarian cancer and other gynecologic cancers. However,
these findings are preliminary and require confirmation in larger studies.
Interleukin 6 mediates the lysophosphatidic acid-regulated cross-talk between stromal and epithelial prostate
cancer cells.
by Perumal Sivashanmugam, Linda Tang, Yehia Daaka
Abstract
The interaction between stromal and epithelial cells is critical for the initiation and progression of prostate cancer,
but the molecular determinants responsible for the cross-talk between these two cell types remain largely unknown.
Here, we used a co-culture cell assay to identify messengers involved in the cross-talk between human prostate
stromal PS30 and epithelial LNCaP cells. Stimulation with lysophosphatidic acid (LPA) activates the mitogenic ERK
signaling pathway in PS30, but not LNCaP, cells. The co-culture of PS30 and LNCaP cells results in the activation of ERK
in LNCaP cells and that is further increased in response to stimulation with LPA. Physiologic relevance of the
interaction between PS30 and LNCaP cells is demonstrated using LNCaP xenograft tumor assays. Animals implanted
with a mixture of both cell types develop larger tumors with higher frequency compared with those injected with
LNCaP cells alone. Conditioned medium transfer experiments reveal the PS30-derived inducing factor is soluble and
promotes mitogenic ERK and STAT3 signaling pathways in LNCaP cells. Protein analysis demonstrates that treatment of
the PS30 cells with LPA induces synthesis of interleukin 6 (IL-6). Antibody neutralization experiments reveal that IL-6 is
responsible for the LPA-induced mitogenic signaling and growth of the LNCaP cells. Our findings reveal that the LPA-
regulated secretion of IL-6 is an important messenger linking stromal and epithelial prostate cells, which may be
exploited for the effective treatment of patients with advanced prostate cancer.
Fatty acid composition of lysophosphatidic acid and lysophosphatidylinositol in plasma from patients with ovarian
cancer and other gynecological diseases.
Shen Z, Wu M, Elson P, Kennedy AW, Belinson J, Casey G, Xu Y.
Source
Department of Cancer Biology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Abstract
OBJECTIVE:
We previously reported that plasma levels of total lysophosphatidic acid (LPA) represented a potential biomarker for
ovarian cancer and other gynecological cancers [1]. However, total LPA is composed of different LPA species with
distinct fatty acid chains. The major objective of the current study, therefore, was to determine whether one or more
specific fatty acid LPA species was associated with disease or disease staging. If this was determined, these species
could be useful in further improving the sensitivity and/or specificity of this biomarker for the diagnosis and/or
prognosis of the disease. Because lysophosphatidylinositol (LPI) co-migrates with LPA, this study represents the
analysis of combined molecular species from both lysolipid classes.
METHODS:
The patient population, sample collection, and analyses have been reported previously [1]. Lipids were hydrolyzed
from the LPA band on thin-layer chromatography plates. The following individual fatty acid species were analyzed by
gas chromatography: palmitic acid (16:0), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2), arachidonic acid
(20:4), and docosahexaenoic acid (22:6). The LPA/LPI fatty acid composition levels were analyzed and compared with
disease status.
RESULTS:
Distinct plasma LPA/LPI fatty acid chain species were not associated with ovarian or other gynecological cancers,
compared to patients with benign gynecological disease or healthy controls. However, an increased presence of
unsaturated fatty acids in plasma LPA/LPI was found in patients with late-stage or recurrent ovarian cancer and
possibly with other gynecological cancers.
CONCLUSIONS:
Analysis of individual fatty acid species present in plasma LPA/LPI do not appear to enhance the sensitivity or
specificity of total LPA/LPI as a marker for gynecological cancer detection. However, our results suggest that
increased LPA/LPI species with unsaturated fatty acid chains may be associated with late-stage or recurrent ovarian
cancer.
nterleukin 6 and its Receptor: Ten Years Later
1998, Vol. 16, No. 3-4 , Pages 249-284
Toshio Hirano†
Department of Molecular Oncology, Biomedical Research Center, Osaka University Medical School, 2–2, Yamada-oka,
Suita, Osaka, 565, Japan
†
Correspondence: Toshio Hirano, 81-6-879-3880, 81-6-879-3889 hirano@molonc.med.osaka-u.ac.jp

Ten years have passed since the molecular cloning of interleukin 6 (IL-6) in 1986. IL-6 is a typical cytokine, exhibiting
functional pleiotropy and redundancy. IL-6 is involved in the immune response, inflammation, and hematopoiesis. The
IL-6 receptor consists of an IL-6 binding α chain and a signal transducer, gp130, which is shared among the receptors
for the IL-6 related cytokine subfamily. The sharing of a receptor subunit is a general feature of cytokine receptors
and provides the molecular basis for the functional redundancy of cytokines. JAK tyrosine kinase is a key molecule that
can initiate multiple signal-transduction pathways by inducing the tyrosine-phosphorylation of the cytokine receptor,
gp130 in the case of IL-6, on which several signaling molecules are recruited, including STAT, a signal transducer and
activator of transcription, and SHP-2, which links to the Ras-MAP kinase pathway. JAK can also directly activate
signaling molecules such as STAT and Tec. These multiple signal-transduction pathways intimately regulate the
expression of several genes including c-myc, c-myb, junB, IRF 1, egr-1, and bcl-2, leading to the induction of cell
growth, differentiation, and survival. The deregulated expression of IL-6 and its receptor is involved in a variety of
diseases.
What are Cytokines?
Cytokines (Greek ''cyto-'', cell; and ''-kinos'', movement) are any of a number of substances that are secreted by
specific cells of the immune system which carry signals locally between cells, and thus have an effect on other cells.
They are a category of signaling molecules that are used extensively in cellular communication. They are proteins,
peptides, or glycoproteins. The term cytokine encompasses a large and diverse family of polypeptide regulators that
are produced widely throughout the body by cells of diverse embryological origin.
Basically, the term "cytokine" has been used to refer to the immunomodulating agents (interleukins, interferons, etc.).
Conflicting data exists about what is termed a cytokine and what is termed a hormone. Anatomic and structural
distinctions between cytokines and classic hormones are fading as we learn more about each. Classic protein hormones
circulate in nanomolar (10) concentrations that usually vary by less than one order of magnitude. In contrast, some
cytokines (such as IL-6) circulate in picomolar (10) concentrations that can increase up to 1,000-fold during trauma or
infection. The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from
hormones. Virtually all nucleated cells, but especially endo/epithelial cells and resident macrophages (many near the
interface with the external environment) are potent producers of IL-1, IL-6, and TNF-α. In contrast, classic hormones,
such as insulin, are secreted from discrete glands (e.g., the pancreas). As of 2008, the current terminology refers to
cytokines as immunomodulating agents. However, more research is needed in this area of defining cytokines and
hormones.
The action of cytokines may be autocrine or paracrine, but not endocrine. The reason for them not being endocrine
signals is that the signal must be released in the general region of the pathogen-infected cells, so other immune
molecules which follow the signal will arrive at that site (where this signal is released). Cytokines are critical to the
development and functioning of both the innate and adaptive immune response, although they are not limited to the
immune system. They are often secreted by immune cells that have encountered a pathogen, thereby activating and
recruiting further immune cells to increase the system's response to the pathogen. Cytokines are also involved in
several developmental processes during embryogenesis.
Cytokine Receptors
In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines
themselves, partly because of their remarkable characteristics, and partly because a deficiency of cytokine receptors
has now been directly linked to certain debilitating immunodeficiency states. In this regard, and also because the
redundancy and pleiomorphism of cytokines are, in fact, a consequence of their homologous receptors, many
authorities think that a classification of cytokine receptors would be more clinically and experimentally useful.
A classification of cytokine receptors based on their three-dimensional structure has, therefore, been attempted. Such
a classification, though seemingly cumbersome, provides several unique perspectives for attractive
pharmacotherapeutic targets.
 Immunoglobulin (Ig) superfamily, which are ubiquitously present throughout several cells and tissues of the
vertebrate body, and share structural homology with immunoglobulins (antibodies), cell adhesion molecules,
and even some cytokines. Examples: IL-1 receptor types.
 Haemopoietic Growth Factor (type 1) family, whose members have certain conserved motifs in their
extracellular amino-acid domain. The IL-2 receptor belongs to this chain, whose γ-chain (common to several
other cytokines) deficiency is directly responsible for the x-linked form of Severe Combined Immunodeficiency
(X-SCID).
 Interferon (type 2) family, whose members are receptors for IFN β and γ.
 Tumor necrosis factors (TNF) (type 3) family, whose members share a cysteine-rich common extracellular
binding domain, and includes several other non-cytokine ligands like CD40, CD27 and CD30, besides the ligands
on which the family is named (TNF).
 Seven transmembrane helix family, the ubiquitous receptor type of the animal kingdom. All G-protein coupled
receptors (for hormones and neurotransmitters) belong to this family. Chemokine receptors, two of which act
as binding proteins for HIV (CXCR4 and CCR5), also belong to this family.
Cytokine Classification
Structural
Structural homology has been able to partially distinguish between cytokines that do not demonstrate a considerable
degree of redundancy so that they can be classified into four types:
 The four α-helix bundle family - Member cytokines have three-dimensional structures with four bundles of α-
helices. This family in turn is divided into three sub-families:
1. the IL-2 subfamily
2. the interferon (IFN) subfamily
3. the IL-10 subfamily.
o The first of these three subfamilies is the largest. It contains several non-immunological cytokines
including erythropoietin (EPO) and thrombopoietin (THPO). Also, four α-helix bundle cytokines can be
grouped into ''long-chain'' and ''short-chain'' cytokines.
o the IL-1 family, which primarily includes IL-1 and IL-18
o the IL-17 family, which has yet to be completely characterized, though member cytokines have a
specific effect in promoting proliferation of T-cells that cause cytotoxic effects
Functional
A classification that proves more useful in clinical and experimental practice divides immunological cytokines into
those that enhance cytokine responses, type 1 (IFN-γ, TGF-β, etc.), and type 2 (IL-4, IL-10, IL-13, etc.), which favor
antibody responses.
A key focus of interest has been that cytokines in one of these two sub-sets tend to inhibit the effects of those in the
other. Dysregulation of this tendency is under intensive study for its possible role in the pathogenesis of autoimmune
disorders.
Several inflammatory cytokines are induced by oxidant stress. The fact that cytokines, themselves trigger the release
of other cytokines and lead also to increased oxidant stress, makes them important in chronic inflamma
Cytokine Nomenclature
Cytokines have been classed as lymphokines, interleukins, and chemokines, based on their presumed function, cell of
secretion, or target of action. Because cytokines are characterised by considerable redundancy and pleiotropism, such
distinctions, allowing for exceptions, are obsolete.
 The term ''interleukin'' was initially used by researchers for those cytokines whose presumed targets are
principally leukocytes. It is now used largely for designation of newer cytokine molecules discovered every day
and bears little relation to their presumed function. The vast majority of these are produced by T-helper cells.
 The term ''chemokine'' refers to a specific class of cytokines that mediates chemoattraction (chemotaxis)
between cells.
IL-8 (interleukin-8) is the only chemokine originally named an interleukin.
Cytokine Effects
Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signalling then alter cell
functions. This may include the upregulation and/or downregulation of several genes and their transcription factors,
resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or
the suppression of their own effect by feedback inhibition.
The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular abundance, the presence
and abundance of the complementary receptor on the cell surface, and downstream signals activated by receptor
binding; these last two factors can vary by cell type. Cytokines are characterized by considerable "redundancy", in that
many cytokines appear to share similar functions.
Generalization of functions is not possible with cytokines. Nonetheless, their actions may be grouped as:
 autocrine : if the cytokine acts on the same type of cell that secretes it.
 paracrine : if the target is restricted to cells of a different type in the immediate vicinity of a cytokine's
secretion.
It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone.
This may lead to lower therapeutic doses.
Oversecretion of cytokines can trigger a dangerous syndrome known as a cytokine storm; this may have been the cause
of severe adverse events during a clinical trial of TGN1412.