Cytokine

Cytokines (Greek cyto-, cell; and -kinos, movement) are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication. Cytokines can be classified as proteins, peptides, or glycoproteins; the term "cytokine" encompasses a large and diverse family of regulators produced throughout the body by cells of diverse embryological origin.^[1]

The term "cytokine" has been used to refer to the immunomodulating agents, such as interleukins and interferons. Biochemists disagree as to which molecules should be termed cytokines and which hormones. As we learn more about each, anatomic and structural distinctions between the two are fading. Classic protein hormones circulate in nanomolar (10^-9) concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines (such as IL-6) circulate in picomolar (10^-12) 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.^[2] In contrast, classic hormones, such as insulin, are secreted from discrete glands (e.g., the pancreas).^[3] 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.

Part of the difficulty with distinguishing cytokines from hormones is that some of the immunomodulating effects of cytokines are systemic rather than local. For instance, to use hormone terminology, the action of cytokines may be autocrine or paracrine in chemotaxis and endocrine as a pyrogen. Further, as molecules, cytokines are not limited to their immunomodulatory role. For instance, cytokines are also involved in several developmental processes during embryogenesis^{[4][nb 1][5][nb 2]}

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.

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.

Said et al. showed that inflammatory cytokines cause an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1 levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.^[6]

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.

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.
  • The first of these three subfamilies is the largest. It contains several non-immunological cytokines including erythropoietin (EPO) and thrombopoietin (TPO). Also, four α-helix bundle cytokines can be grouped into long-chain and short-chain cytokines.
• the IL-1 family, which primarily includes IL-1 and IL-18
• 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 cellular immune 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.^[7][8] The fact that cytokines themselves trigger the release of other cytokines^[9][10] and also lead to increased oxidant stress makes them important in chronic inflammation.

Cytokine receptors

Main article: Cytokine receptor

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^{[citation needed]}.

Disease

Adverse effects of cytokines have been linked to many disease states and conditions ranging from major depression^[11] and Alzheimer's disease^[12] to cancer^[13] with levels either being elevated or changed. 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.

Plasma levels

Plasma levels of various cytokines may give information on the presence, or even predictive value of inflammatory processes involved in autoimmune diseases such as rheumatoid arthritis,^[14] as well as immunomodulatory effects of foods or drugs.^[15] In addition, elevated levels of IL-7, an important cytokine involved in T cell homeostasis, have been detected in the plasma of HIV-infected patients.^[16]

Cysteine-knot cytokines

Members of the transforming growth factor beta superfamily belong to this group, including TGF-β1, TGF-β2 and TGF-β3.

See also

• Active Hexose Correlated Compound
• Adipokines
• Apoptosis
• Cytokine secretion assay
• Cytokine storm
• ELISA assays
• ELISPOT assays
• FluoroSpot assays
• Granulocyte-colony stimulating factor
• Signal transduction
• Interleukin-7
• TSLP

Notes

1. ^ Saito explains "much evidence has suggested that cytokines and chemokines play a very important role in the reproduction, i.e. embryo implantation, endometrial development, and trophoblast growth and differentiation by modulating the immune and endocrine systems."(15)
2. ^ Chen explains the regulatory activity of LIF in human and murine embryos: "In conclusion, human preimplantation embryos express LIF and LIF-R mRNA. The expression of these transcripts indicates that preimplantation embryos may be responsive to LIF originating either from the surrounding environment or from the embryos themselves and exerting its function in a paracrine or autocrine manner."(719)

References

1. ^ Gilman A, Goodman LS, Hardman JG, Limbird LE (2001). Goodman & Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill. ISBN 0-07-135469-7. 
2. ^ Boyle, J. J. (2005). Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. Curr Vasc Pharmacol, 3(1), 63-68. PMID=15638783
3. ^ Cannon JG (2000). "Inflammatory Cytokines in Nonpathological States". News Physiol Sci. 15: 298–303. PMID 11390930. 
4. ^ Saito, Shigeru (October–November 2001). "Cytokine cross-talk between mother and the embryo/placenta". Journal of Reproductive Immunology 52 (1–2): 15–33. doi:10.1016/S0165-0378(01)00112-7. PMID 11600175. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T8W-445B4KX-3&_user=10&_coverDate=11%2F30%2F2001&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1271989808&_rerunOrigin=scholar.google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=cdad0fbe5c489efea109a3025c282e44. Retrieved 2010-03-29. 
5. ^ Chen M.D., Hsin-Fu; Jin-Yuh Shew, Hong-Nerng Ho, Wei-Li Hsu, Yu-Shih Yang (October 1999). "Expression of leukemia inhibitory factor and its receptor in preimplantation embryos". Journal of Reproductive Biology 72 (4): 713–719. doi:10.1016/S0015-0282(99)00306-4. http://linkinghub.elsevier.com/retrieve/pii/S0015028299003064. Retrieved 2010-03-29. 
6. ^ Elias A. Said et al. 2009, PD-1 Induced IL10 Production by Monocytes Impairs T-cell Activation in a Reversible Fashion. Nature Medicine. 2010; 452-9.
7. ^ Vlahopoulos, S; Boldogh, I; Casola, A; Brasier, AR (1999). "Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation". Blood 94 (6): 1878–89. PMID 10477716. 
8. ^ David, F; Farley, J; Huang, H; Lavoie, JP; Laverty, S (2007). "Cytokine and chemokine gene expression of IL-1beta stimulated equine articular chondrocytes". Veterinary surgery : VS 36 (3): 221–7. doi:10.1111/j.1532-950X.2007.00253.x. PMID 17461946. 
9. ^ Carpenter, LR; Moy, JN; Roebuck, KA (2002). "Respiratory syncytial virus and TNF alpha induction of chemokine gene expression involves differential activation of Rel A and NF-kappa B1". BMC infectious diseases 2: 5. PMC 102322. PMID 11922866. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=102322. 
10. ^ Tian, B; Nowak, DE; Brasier, AR (2005). "A TNF-induced gene expression program under oscillatory NF-kappaB control". BMC genomics 6: 137. doi:10.1186/1471-2164-6-137. PMC 1262712. PMID 16191192. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1262712. 
11. ^ Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL (2010). "A meta-analysis of cytokines in major depression". Biol Psychiatry 67 (5): 446–457. doi:10.1016/j.biopsych.2009.09.033. PMID 20015486. 
12. ^ Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010). "A meta-analysis of cytokines in Alzheimer's disease". Biol Psychiatry 68 (10): 930–941. doi:10.1016/j.biopsych.2010.06.012. PMID 20692646. 
13. ^ Locksley RM, Killeen N, Lenardo MJ (2001). "The TNF and TNF receptor superfamilies: integrating mammalian biology". Cell 104 (4): 487–501. doi:10.1016/S0092-8674(01)00237-9. PMID 11239407. 
14. ^ Kokkonen, H. Arthritis & Rheumatism, Feb. 2, 2010; vol 62: pp 383-391
15. ^ Nikolaeva LG, Maystat TV, Masyuk LA, Pylypchuk VS, Volyanskii YL, Kutsyna GA (2009). "Changes in CD4+ T-cells and HIV RNA resulting from combination of anti-TB therapy with Dzherelo in TB/HIV dually infected patients". Drug Des Devel Ther 2: 87–93. PMC 2761183. PMID 19920896. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2761183. 
16. ^ Napolitano LA, Grant RM, Deeks SG, et al. (January 2001). "Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis". Nat. Med. 7 (1): 73–9. doi:10.1038/83381. PMID 11135619. 

External links

• Cytokine Gene Summary, Ontology, Pathways and More - Immunology Database and Analysis Portal (ImmPort)
• Cytokine Tutorial. dead link.
• Cell Interactions: Cytokines. inactive link
• Reperfusion Injury in Stroke.
• CopeWithCytoKines Cytokines Online Pathfinder Encyclopaedia