cytokines

Review/Biological and Biomedical Reports (ISSN: 2162-4186), 2012, 2(1), 37-43

ABSTRACT The article is an overview of different properties of cytokines. It discusses ways to group these proteins, major advancements regarding their structure, functions and significance in the last three or four decades, the newly diagnosed cytokines and their major contribution, various clinical conditions where the role of these proteins have been established and also the clinical situations where these cytokines are being used for therapeutic purposes. Keywords: autoimmunity; T helper cells; chemokines; interleukins; T regulatory cells; immunodeficiency Cytokines are small secreted signaling proteins produced de novo in response to an immune stimulus that mediate and regulate immunity, inflammation and hematopoiesis. They are produced by different hematopoietic and non-hematopoietic cells, but the predominant source is T helper cells and macrophages. They generally, but not always act over short distances, for short intervals and at low concentration. Cytokines are critical for innate and adaptive immune responses. They activate and recruit immune cells and increase responses against foreign pathogens. They also play role in development and functioning of immune system. Their aberrant mode of secretion is documented in a variety of immunological, inflammatory and infectious diseases.

Cytokines effect on a cell depends on its extra cellular abundance, complementary receptors and production of downstream signals. They are characterized by considerable redundancy, as many cytokines share similar functions while over stimulation of cytokines can trigger a dangerous syndrome known as cytokine strom; may be the cause of severe adverse events during a clinical trial (1,2). Cytokine field is becoming ever more complex and it is not possible in a single volume to present all the new facts and concepts, about these proteins. This review article is an attempt to cover some of the areas in which new information has appeared or where new interpretations and concepts are emerging. During 19501970 cytokine studies involved description of protein factors produced by different cells that mediate particular functions such as antiviral interferon, fever producing pyrogens, etc. Later, partial purification, characterization of many individual cytokines and production of specific neutralizing antisera was done. Golden age of cytokine research occupied 1980s which characterized molecular cloning, expression of cytokine molecules and production of specific, monoclonal, neutralizing antibodies. These reagents allowed identification of structure and properties of individual cytokines. Many new cytokines were discovered and previously unexpected properties of known cytokines were revealed. As a result of these studies, there is now a

Biological and Biomedical Reports, 2012, 2(1), 37-43 Review Cytokines: an ever expanding area Nadeem Afzal1,*, Romeeza Tahir1, Shah Jahan1 1. Department of Immunology, University of Health Sciences Lahore, Lahore-54600, Pakistan Corresponding author*: [email protected] __________________________________________________________________________________


wealth of information about the sources and biologic activities of particular cytokines (2,3). Cytokines also called as lymphokine, monokine, chemokine, and interleukin (IL). They are autocrine, paracrine or endocrine in action. There may be pleiotropic, redundant, cascade, synergistic or antagonistic functions of cytokines. They are grouped as working on natural immunity, pro-inflammatory, non-inflammatory or involved in lymphocyte activation, growth and differentiation or involved in immune mediated inflammation. Redundancy and pleiomorphism of cytokines is a consequence of their homologous receptors. Dysregulation of cytokines is under intensive study for their possible role in pathogenesis of autoimmune disorders (2,3,4). Cytokine bind to specific cell-surface receptors that lead to subsequent cascade of intracellular signaling. There is up-regulation or down-regulation of several genes and their transcription factors, production of other cytokines, an increase of surface receptors, or suppression of their own effects by feedback inhibition. Cytokine receptors are classified as immunoglobulin superfamily, haemopoietic growth factor (type 1), interferon (type 2), tumor necrosis factor (type 3) and seven transmembrane helix family. Cytokine receptors deficiency has been linked to certain immunodeficiency states (5,6). Structural homologies classify cytokines into four alpha-helix bundle family, which is divided into three sub-families: IL-2, interferon and IL-10 subfamily. IL-2 is a T cell growth factor; it controls peripheral tolerance and NK cell activity. IL-2R subfamily consists of receptors for IL-2, IL-4, IL-7, IL-9, IL-13, IL-15 and IL-21, has a common signal-transducing gamma chain. A defect in IL-2R family gamma chain may lead to X-linked severe combined immunodeficiency (XSCID). Lack of T cells and NK cells in XSCID is explained by lack of

IL-7 and IL-15 signaling respectively, whereas defective signaling by IL-4 and IL-21 contributes to B cell defect. IL-21 is involved in proliferation, differentiation and effector functions of B, T, NK and dendritic cells. It may promote or inhibit immune responses and its potential therapeutic capacity in treating cancers is being investigated (6-10). T helper cells are broadly divided into Th1 and Th2; functionally distinct subsets that secrete different cytokines, rather cytokines are critical mediators of this polarization. IFN-gamma and IL-12 promote Th1 activities while IL-4 and IL-10 stimulate Th2 cell population. Th1 produces cytokines that activate cytotoxic T cells, macrophages and stimulate B cells to secrete IgG2a and inhibit IgG1 and IgE. Similarly, Th2 cells secrete cytokines that stimulate B cells to produce antibodies; IgE and IgG1. Th1 and Th2 cytokines are antagonistic in activity (4,11,12). T regulatory cells (Treg) are a group of cells that control autoimmunity and T cell homeostasis. On the basis of distinct phenotype, cytokine profile and mechanism of action several types of Treg cells are identified such as gamma-delta T cell, natural killer T cells, CD4+ and CD8+ T cells. Their suppressive activity is associated with IL-10, and TGF-b (3,13,14,15). Th17 is a newly diagnosed subset of CD4+ T cells with significant pro-inflammatory functions which produces IL-17; a family of six cytokines (IL-17A - F). IL-17 play a central role in autoimmune diseases, promotes cytotoxic T cells and its mRNA is found in tissues/biological fluids of RA, SLE, uveitis/scleritis, inflammatory bowel disorders and psoriasis patients (2, 16, 17, and 18). IL-17 recruits neutrophils and facilitate granuloma formation and priming of Th17 cells require IL-1beta and IL-6. TGF-beta promotes murine IL-17 expression but human IL-17 may be down-regulated by this cytokine. IL-17 mobilizes neutrophils from bone marrow and promotes


production of IL-1, IL-6 and TNF, which are important for controlling acute infections. IL-17 family is not completely characterized yet (13, 14, 15, and 19). Lineage commitment and functions of various T cell populations has been shown in Figure 1 (16).

Figure 1. Different T cell populations and their functions IL-25 formerly known as IL-17E is a member of IL-17 family; which is a Th2 like cytokine. Unlike IL-17, IL-25 is produced by Th2 cells and mast cells. IL-25-/- mice showed susceptibility to parasitic helminthes; associates with impaired IL-4 and IL-13 production and reduced parasite specific IgG1 and total IgE. Antihelminth activity of IL-25 depends on its ability to induce Th2 associated cytokines. It is also anti-inflammatory in suppressing Th1 and Th17 responses. IL-25 may not be absolutely required for the generation of Th2 responses in some parasitic infections but is important for timely resolution of infection. Expression of IL-25 is very limited; CD4+ and CD8+ in gut showed existence of effector T cells that selectively produce IL-25; it suggests a special role of IL-25 in mucosal immunity (20,21). IL22 like IL-17, is another pro-inflammatory cytokine which acts on non-immunological tissues and is associated with chronic T cell mediated inflammatory diseases e.g. psoriasis, Crohns disease and RA. Expression of IL-22 receptor; IL-22R1, is detected in many tissues

such as epithelial cells of lung, implicating its role in pulmonary inflammation (18). CD4+ T cells are predominant source of IL-17 and IL-22 but they are distinct from each other and are distinct from Th1 cytokine producing subsets. Th1 cytokines inhibit IL-17, but not IL-22, therefore it is suggested that regulation of IL-17 and IL-22 producing cells are different. T cells showed a strong tendency for mutually exclusive production of INF-gamma or IL-17 (12, 15, 22, and 23). IL-23 a new regulatory cytokine of IL-12 family is produced by activated macrophages and dendritic cells. IL-12 and IL-23 bridge innate and adaptive immunity as IL-12 is required for antimicrobial responses to intracellular pathogens, whereas IL-23 recruits and activates various inflammatory cells for induction of chronic inflammation and granuloma formation. IL-12 receptor is composed of IL-12R-beta1 and IL-12R-beta-2, whereas IL-23 binds to receptor composed of IL-12R-beta-1 and IL-23. Therefore targeting IL-12 and IL-23 and their downstream signaling elements would be logical strategies for treatment of immune mediated diseases. IL-12 and IL-23 are indeed master regulators of innate and adaptive immunity but we still have to find out design of effective therapeutics that could specifically inhibit right target IL-12, IL-17, IL-23 or others for a range of immune mediated inflammatory disorders (23). Experimental autoimmune encephalitis and collagen induced arthritis develop in mice which are deficient in either IL-12 or IL-23. Further, mice lacking IL-12 receptor complex succumbed to disease meaning it is IL-23 and not IL-12 required for the disease. It established an inverse relation between Th1 induction and disease development and a positive correlation between IL-23 and development of effector CD4+ T cells that produce IL-17; a cytokine linked to IL-23 induced inflammation. Similarly, IL-17 deficient mice demonstrated impaired joint inflammation and neutralization of IL-17


decreases disease severity. Therefore, in some autoimmune disorders, it is IL-23-IL-17 cytokine axis, and not IL-12-INF-gamma-axis crucial for disease (14,23,24,25). TNF-alpha, stimulates IL-1 and IL-6 but suppresses bone marrow stem cell division. Chronic administration of TNF-alpha may lead to lymphopenia, immunodeficiency and rheumatoid arthritis patients showed increased risk of tuberculosis. IL-1 does not cause tissue injury by itself, but it can potentiate injury along with TNF. IL-6 is a growth factor for activated B and malignant plasma cells. It may serve as a co-stimulator of T cells and is required for bone marrow hematopoietic stem cells. TGF-beta is pleiotropic, inhibit growth of many cells while stimulate others. It causes angiogenesis and may act as pro-inflammatory (IL-17 inducing) or anti-inflammatory (Th3) agent and shut off immune response but some tumors escape immune responses by secreting large quantities of TGF-beta (2,10,13,15,17,26). IL-4 is a growth and differentiation factor for Th2 cells. It synergizes with IL-3 in stimulating mast cells in allergic reactions and switching of B cells to IgE heavy chain isotype. IL-4 stimulates expression of certain adhesion molecules such as VCAM-1 on endothelial cells and inhibits macrophage activation (4). INF-gamma secretion starts with antigen activation and is enhanced by IL-2 and IL-12. INF-gamma an anti-viral cytokine stimulates cytolytic activity of NK cells and is an anti-tumor agent (with TNF). It increases MHC class I and II expression, therefore increases cellular and humoral immune responses. It promotes T and B cell differentiation; favors Th1 and inhibits Th2 responses (13,22). IL-10 may act as immunostimulatory or immunosuppressive factor. It stimulates innate immune system; NK and B cells and inhibits TNF, IL-1, chemokines and IL-12 by

macrophages. Increased IL-10 play a role in early control of viral infection and tumor cell dissemination but later it decreases both innate and adoptive responses (27,28). IL-27 is structurally and functionally similar with IL-12, is pro-inflammatory and it may promote Th1 responses. Its stimulatory and inhibitory effects are in parallel of many other cytokines (19, 29). Cytokine inhibition as treatment: In Alzheimers disease (AD) inflammatory processes lead to neurotoxicity. It is a group of functionally interrelated cytokines and TNF-alpha is crucial as it is elevated in patients cerebrospinal fluid and serum. There is activation of microglia which releases many cytokines that may lead to neuronal death and its dysfunction. A single nucleotide polymorphism in TNF-alpha gene is associated with earlier onset of AD. Amyloid-specific IL-10 generation is selectively and significantly reduced in AD patients. Analyses of alleles of IL-10 gene revealed, high IL-10 production is extremely infrequent in AD individuals. Presence of low/intermediate IL-10-producing genotypes (GCC/ATA; ATA/ATA) is associated with early age onset of disease and (ACC/ACC; ACC/ATA) with an accelerated rate of disease progression. Therapeutic strategies that affect microglial activation or proinflammatory cytokine release or anti-amyloid therapies are in development (30,31). Allergic Diseases: extensively used anti-inflammatory agent is corticosteroid, which act on mast cells, eosinophils and effect cytokine production. TNF-alpha production by mast cells is down regulated by corticosteroids. Successful allergen immunotherapy is characterized by a switch of allergen-specific Th2 to Th1 expression (13,32). Recombinant cytokines are studied in a variety of malignant, infectious, autoimmune and


allergic/asthmatic diseases. They are expensive, toxic and since a disease is an imbalance of "good" and "bad" cytokines, giving large doses of recombinant cytokines may create further imbalances. Recombinant cytokines are successful in atopic dermatitis; IFN-gamma in children with severe atopic dermatitis. During desensitization IFN-gamma to pollens may act on animal dander-specific TH2 clone to down regulate its activity. Marillion Pharmaceuticals Inc has recently got the permission to develop and commercialize cytokine's treatment for xerostomia (10). IL-13 regulates inflammation, mucus production, tissue remodeling and fibrosis. It induces allergic response via a complex array rather through immunoglobulin-E and eosinophils. It is important therapeutic target for asthma, idiopathic pulmonary fibrosis, ulcerative colitis, etc. A schistosomiasis model illustrated opposing activities for IL-13 and IL-13R-alph-2 in health and disease; IL-13R-alpha-2 is down regulated in granulomatous inflammatory response. IL-13 is overproduced in many chronic and allergic diseases; the amount of free versus IL-13R-alpha-2-bound IL-13 may be a key to pathogenesis of a variety of Th2 mediated diseases (32). Chronic inflammatory diseases: It is seen that combination of anti-TNF-alpha and anti-CD4 can be useful in collagen arthritis (CIA). TNF receptor-1 associated syndrome (TRAPS) is a chronic inflammatory disorder with mutations in 55 kDa TNFRSFIA gene. IL-1beta blockade showed improvement in a TRAPS French patient who failed to respond to anti-TNF-alpha therapy (13). Chronic heart failure: Patients have high level of many cytokines and they may negatively influence contractility of heart. Intravenous immunoglobulin (IVIG) therapy showed improvement as it may down regulate chemokines and their receptors. Several anti-cytokine and immunomodulatory therapy, in addition to conventional cardiovascular

treatment regimens, have recently emerged as possible promising treatment modalities (33). Endothelial cells are activated by cytokine treatment to kill an intravascular parasite Schistosoma mansoni, through production of nitric oxide: INF-gamma, TNF-alpha, IL-1alpha and IL-1beta kill Schistosoma mansoni through an arginine-dependent mechanism involving production of nitric oxide (NO). NO-dependent reactions also kill tumor cells and inhibit intracellular growth of protozoan parasite Toxoplasma gondii (21). Autoimmunity from cytokine treatment predicts long-term survival in metastatic renal cell cancer: Recombinant IL-2 and INF-alpha-2 showed promising results as they may alter immune responsiveness in genetically predisposed patients (27). Future prospects for anti-cytokine treatment: In rheumatology an era of anti-cytokine treatment has just begun. First generation biological agents block TNF-alpha such as monoclonal antibodies or receptor Ig fusion proteins are safe and effective. The efficacy, safety and capacity of anti-TNF-alpha therapeutic agents (infliximab, etanercept and D2E7) are widely documented. Anti-TNF-alpha is effective in all aspects of rheumatoid arthritis. Interestingly, there was joint protection even in patients who did not respond clinically, suggesting no clear distinction between anti-TNF-alpha responders and non-responders. Further, IL-1 and not TNF-alpha is most important cytokine in joint destruction. IL-12 is inducer of Th1 and is very beneficial in early induction phase. Both anti IL-12 and TNF-alpha may act in synergy at inhibiting inflammation and in protecting joints. IL-15 activates T cells in antigen non-specific manner and its inhibition might synergize with anti TNF-alpha. IL-18 (now known to be IL-1) has much broader effects and is a potential target, together with IL-12 with which it synergizes. Oncostatin M is a member of IL-6


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