An Overview of Cytokine Regulation of Inflammation and Immunity


The defence of an organism depends on the recognition of harmful stimuli followed by appropriate activation of innate and adaptive immune responses. Primary recognition of harmful stimuli is mediated by specific receptors of monocytes, macrophages and dendritic cells, leading to cytokine production. Several cytokines have proinflammatory actions that drive the innate immune response, cause inflammation and activate adaptive immune responses. Further activation of adaptive immunity depends on cytokine regulation of T‐cell differentiation into specific T‐cell subsets with specific roles in defence against the invading pathogens. Although cytokine regulation of inflammation and immunity is crucial for protection against infection and injury, their actions in excess are associated with a variety of autoinflammatory and autoimmune diseases.

Key Concepts:

  • Cytokines are a broad class of biologically active proteins with hormone‐like actions that are produced in response to homoeostatic, and more particularly harmful, stimuli.

  • The extent of cytokine production is dependent both on the nature of the stimulus and on regulatory intracellular mechanisms.

  • Cytokines may act on any cells that bear receptors, by which, with the involvement of signal transduction pathways, nuclear gene transcription is activated.

  • Many cytokines act on cells of the immune and vascular systems to regulate cell proliferation, differentiation and activation of pro‐ or anti‐inflammatory mechanisms.

  • Monocytes, macrophages and dendritic cells bear ‘pattern recognition receptors’ and are especially sensitive to harmful stimuli such as pathogens bearing ‘pathogen‐associated molecular patterns (PAMPs)’.

  • Monocytes and macrophages produce the proinflammatory cytokines, for example, interleukin‐1, tumour necrosis factor‐α, responsible for inflammatory reactions and innate immune responses.

  • Cytokines such as interleukin‐12, interleukin‐18 and interleukin‐23 couple the innate immune response to adaptive immune responses mediated by T cells, B cells and natural killer cells.

  • T‐cell differentiation into specific T‐cell subsets is governed by several cytokines, for example, interleukin‐4 and interferon‐gamma, acting antagonistically to one another.

  • Excessive cytokine production or action leads to acute or chronic inflammation, which may trigger autoinflammatory and autoimmune diseases in the long term.

Keywords: cytokine; interleukin; inflammation; immunity; monocyte; macrophage; T cell; natural killer cell

Figure 1.

Schematic diagram illustrating the proposed interactions of pro‐ (black) and anti‐ (red) inflammatory interleukins and other cytokines in the mediation of acute and chronic inflammation. The chemokine IL‐8 released from macrophages and APCs forms a chemotactic gradient to attract neutrophils (N) to sites of injury and infection. The expression of cellular adhesion molecules, for example, intercellular adhesion molecule‐1 (ICAM‐1), is markedly increased by IL‐1β, IL‐17A and TNFα leading to neutrophil adherence to the endothelial cells lining the blood capillaries, following which N transmigrate into the injured/infected tissue. Neutrophils and T‐cell infiltrates (not shown) release more proinflammatory ILs and cytokines to resolve the injury/infection, but which may lead, if not appropriately regulated, to aggressive T cell‐mediated attack on host tissues and ultimately to profound autoimmune disease. TRegs act to dampen excessive immune attack by releasing IL‐10 and TGF‐β1, which inhibit TH17 cell activation.

Figure 2.

Schematic diagram of the proposed cytokine‐regulated pathways for the differentiation and development of functional T‐cell subsets. Each TH subset expresses a unique ‘portfolio’ of ILs and other cytokines that pertains to their function: TH1 subset upregulates cell‐mediated immunity; TH2 subset provides ‘help’ for humoral immune responses, including immunoglobulin production from B cells and mast cells; TH17 subset probably provides ‘early’ defence against large injuries and infections. CD8+ T cells form the majority of CTL, which attack and kill foreign antigen‐presenting cells. Once the injury/infection is resolved, the functional responsiveness of T cells is shutdown by IL‐10 and TGFβ1 secreted by TReg. Memory T cells then may develop, which are sustained by IL‐7.



Adolf GR , Pieler C and Maurer‐Fogy I (1992) Constitutive production of interferon‐alpha 2 by a human B‐lymphoblastoid cell line. Journal of Interferon Research 12: 275–280.

Akira S , Taga T and Kishimoto T (1993) Interleukin‐6 in biology and medicine. Advances in Immunology 54: 1–78.

Alber G , Al‐Robaiy S , Kleinschek M et al. (2006) Induction of immunity and inflammation by interleukin‐12 family members. Ernst Schering Research Foundation Workshop 56: 107–127.

Aujla SJ and Kolls JK (2009) IL‐22: a critical mediator in mucosal host defense. Journal of Molecular Medicine 87: 451–454.

Banchereau J , Pascual V and O'Garra A (2012) From IL‐2 to IL‐37: the expanding spectrum of anti‐inflammatory cytokines. Nature Immunology 13: 925–931.

Bacchetta R , Passerini L , Gambieri E et al. (2006) Defective regulatory and effector T cell functions in patients with FOXP3 mutations. Journal of Clinical Investigation 116: 1713–1722.

Banham AH (2006) Cell‐surface IL‐7 receptor expression facilitates the purification of FOXP3+ regulatory T cells. Trends in Immunology 27: 541–544.

Batten M , Li J , Yi S et al. (2006) Interleukin‐27 limits autoimmune encephalomyelitis by suppressing the development of interleukin‐17‐producing T cells. Nature Immunology 7: 929–936.

Bettelli E , Carrier Y , Gao W et al. (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441: 235–238.

Bradley LM , Haynes L and Swain SL (2005) IL‐7: maintaining T‐cell memory and achieving homeostasis. Trends in Immunology 26: 172–176.

Budagan V , Bulanova E , Paus R and Bulfone‐Paus (2006) IL‐15/IL‐15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Reviews 17: 259–280.

Cavani A , Pennino D and Eyerich K (2012) Th17 and Th22 in skin allergy. Chemical Immunology and Allergy 96: 39–44.

Chackerian AA , Chen S‐J , Brodie SJ et al. (2006) Neutralization or absence of the interleukin‐23 pathway does not compromise immunity to mycobacterial infection. Infection and Immunology 74: 6092–6099.

Crow YJ (2010) Type I interferonopathies: a novel set of inborn errors of immunity. Annals of the New York Academy of Sciences 1238: 91–98.

Crow YJ and Rehwinkel J (2009) Aicardi–Goutières syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Human Molecular Genetics 18(Review issue 2): R130–R136.

Di Cesare A , Di Meglio P and Nestle FO (2009) The IL‐23/ Th17 axis in the immunopathogenesis of psoriasis. Journal of Investigative Dermatology 129: 1339–1350.

Dinarello CA (2002) The IL‐1 family and inflammatory diseases. Clinical and Experimental Rheumatology 20(Suppl. 27): S1–S13.

Dinarello CA , Novick D , Rubinstein M and Lonnemann G (2003) Interleukin 18 and interleukin 18 binding protein: possible role in immunosuppression of chronic renal failure. Blood Purification 21: 258–270.

Dinarello CA , Simon A and van der Meer JW (2012) Treating inflammation by blocking interleukin‐1 in a broad spectrum of diseases. Nature Reviews Drug Discovery 11: 633–652.

Duhen T , Geiger R , Jarrossay D , Lanzavecchia A and Sallusto F (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin‐homing memory T cells. Nature Immunology 10: 857–863.

Duvallet E , Semerano L , Assier E , Falgarone G and Boissier MC (2011) Interleukin‐23: a key cytokine in inflammatory diseases. Annals of Medicine 43: 503–511.

Elyaman W , Bradshaw EM , Uyttenhove C et al. (2009) IL‐9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory cells. Proceedings of the National Academy of Sciences of the USA 106: 12885–12890.

Eyerich S , Eyerich K , Pennino D et al. (2009) Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodelling. Journal of Clinical Investigation 119: 3573–3585.

Gapin L (2009) Where do MAIT cells fit into the family of unconventional T cells? PLoS Biology 31: e70.

Gilliet M , Cao W and Liu YJ (2008) Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nature Reviews Immunology 8: 594–606.

Glimcher LH and Murphy KM (2000) Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes and Development 14: 1693–1711.

Habib T , Nelson A and Kaushansky K (2003) IL‐21: a novel IL‐2‐family lymphokine that modulates B, T, and natural killer cell responses. Journal of Allergy and Clinical Immunology 112: 1033–1045.

Hoeve MA , Savage ND , de Boer T et al. (2006) Divergent effects of IL‐12 and IL‐23 on the production of IL‐17 by human T cells. European Journal of Immunology 36: 661–670.

Huber JP and Farrar JD (2011) Regulation of effector and memory T‐cell function by type 1 interferon. Immunology 132: 466–474.

Ito T , Kanzler H , Duramad O , Cao W and Liu YJ (2006) Specialization, kinetics and repertoire of type I interferon responses by human predendritic cells. Blood 107: 2423–2431.

Iwasaki A and Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327: 291–295.

Jacques C , Gosset M , Berenbaum F and Gabay C (2006) The role of IL‐1 and IL‐1Ra in joint inflammation and cartilage degradation. Vitamins and Hormones 74: 371–403.

Kikly K , Liu L , Na S and Sedgwick JD (2006) The IL‐23/Th(17) axis: therapeutic targets for autoimmune inflammation. Current Opinions in Immunology 18: 670–675.

Koreth J , Matsuoka K , Kim HT et al. (2011) Interleukin‐2 and regulatory T cells in graft‐versus‐host disease. New England Journal of Medicine 365: 2055–2066.

Kosaka Y , Felices M and Berg LJ (2006) Itk and TH2 responses: action but no reaction. Trends in Immunology 27: 453–460.

Kühn R , Lohler J , Rennick D et al. (1993) Interleukin‐10‐deficient mice develop chronic enterocolitis. Cell 75: 263–274.

Kumagai Y and Akira S (2010) Identification and functions of pattern‐recognition receptors. Journal of Allergy and Clinical Immunology 125: 985–992.

La Cava A , van Kaer L and Dong‐Shi F (2006) CD4+ CD25+ Tregs and NKT cells: regulators regulating regulators. Trends in Immunology 27: 322–327.

Lamkanfi M and Dixit VM (2009) The inflammasomes. PLoS Pathogens 5(12): e1000510.

Langowski JL , Zhang X , Wu L et al. (2006) IL‐23 promotes tumour incidence and growth. Nature 442: 461–465.

Le Bourhis L , Guerri L , Dusseaux M et al. (2011) Mucosal‐associated invariant T cells: unconventional development and function. Trends in Immunology 32: 212–218.

Liu JZ , Pezeshki M and Raffatellu M (2010) Th17 cytokines and host pathogen interactions at the mucosa: dichotomies of help and harm. Cytokine 48: 156–160.

Lizee G , Radvanyi LG , Overwijk WW and Hwu P (2006) Improving antitumour immune responses by circumventing immunoregulatory cells and mechanisms. Clinical Cancer Research 12: 4794–4803.

Ma A , Koka R and Burkett P (2006) Diverse functions of IL‐2, IL‐15, and IL‐7 in lymphoid homeostasis. Annual Reviews of Immunology 24: 657–679.

Malek TR and Pugliese A (2011) Low‐dose IL‐2 as a therapeutic agent for tolerance induction. Immunotherapy 3: 1281–1284.

Matsuyama M , Sairenji T , Yonemura K and Hinuma Y (1982) Interferon production potentials of various human lymphoblastoid cell lines. Microbiology and Immunology 26: 1149–1158.

McKenzie BS , Kastelein RA and Cua DJ (2006) Understanding the IL‐23‐IL‐17 immune pathway. Trends in Immunology 27: 17–23.

Medzhitov R (2007) Recognition of microorganisms and activation of the immune response. Nature 449: 819–826.

Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454: 428–435.

Moschen AR , Geiger S , Krehan I , Kaser A and Tilg H (2008) Interferon‐alpha controls IL‐17 expression in vitro and in vivo . Immunobiology 213: 779–787.

Mosmann TR , Cherwinski H , Bond MW , Giedlin MA and Coffman RL (1986) Two types of murine T cell clone. 1. Definition according to profiles of lymphokine activities and secreted proteins. Journal of Immunology 136: 2348–2357.

Nagarajan UM (2011) Induction and function of IFNβ during viral and bacterial infection. Critical Reviews in Immunology 31: 459–474.

Nossal GJ (1994) Negative selection of lymphocytes. Cell 76: 229–239.

Notarangelo LD , Gambineri E and Badolato R (2006) Immunodeficiencies with autoimmune consequences. Advances in Immunology 89: 321–370.

Nowak EC , Weaver CT , Turner H et al. (2009) IL‐9 as a mediator of Th17‐driven inflammatory disease. Journal of Experimental Medicine 206: 1653–1660.

Ombrello MJ and Kastner DL (2011) Autoinflammation in 2010: Expanding clinical spectrum and broadening therapeutics. Nature Reviews Rheumatology 7: 82–84.

Ramgolam VS , Sha Y , Jin J , Zhang X and Markovic‐Plese S (2009) IFN‐β inhibits human Th17 cell differentiation. Journal of Immunology 183: 5418–5427.

Reantragoon R , Kjer‐Nielsen L , Patel O et al. (2012) Structural insights into MR1‐mediated recognition of the mucosal‐associated invariant T cell receptor. Journal of Experimental Medicine 209: 761–774.

Rogge L , Barberis‐Maino L , Biffi M et al. (1997) Selective expression of an interleukin‐12 receptor component by human T helper 1 cells. Journal of Experimental Medicine 185: 825–831.

Saadoun D , Rosenzwajg M , Joly F et al. (2011) Regulatory T‐cell responses to low dose interleukin‐2 in HCV‐induced vasculitis. New England Journal of Medicine 365: 2067–2077.

Sahoo M , Ceballos‐Olvera I , del Barrio L and Re F (2011) Role of the inflammasome, IL‐1β, and IL‐18 in bacterial infections. The Scientific World Journal 11: 2037–2050.

Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self‐tolerance and negative control of immune responses. Annual Reviews In Immunology 22: 531–562.

Salloum R and Niewold TB (2011) Interferon regulatory factors in human lupus pathogenesis. Translational Research 157: 326–331.

Sospedra M and Martin R (2005) Immunology of multiple sclerosis. Annual Reviews In Immunology 23: 683–747.

Strober W and Fuss IJ (2011) Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140: 1756–1767.

Strowig T , Henao‐Mejia J , Elinav E and Flavell R (2012) Inflammosomes in health and disease. Nature 481: 278–286.

Stumhofer JS , Laurence A , Wilson EH et al. (2006) Interleukin 27 negatively regulates the development of interleukin 17‐producing T helper cells during chronic inflammation of the central nervous system. Nature Immunology 7: 937–945.

Takaoka A , Yanai H , Kondo S et al. (2005) Integral role of IRF‐5 in the gene induction programme activated by Toll‐like receptors. Nature 434: 243–249.

Takeuchi O (2012) IRF‐3: a molecular switch in pathogen responses. Nature Immunology 13: 634–635.

Tamura T , Yanai H , Savitsky D and Taniguchi T (2008) The IRF family transcription factors in immunity and oncogenesis. Annual Reviews In Immunology 26: 535–584.

Theophilopoulos AN (1995) The basis of autoimmunity: Part I. Mechanisms of aberrant self‐recognition. Immunology Today 16: 90–98.

Umetsu DT , Jabara HH , DeKruyff RH et al. (1988) Functional heterogeneity among human inducer T cell clones. Journal of Immunology 140: 4211–4216.

Volin MV and Koch AE (2011) Interleukin‐18: a mediator of inflammation and angiogenesis in rheumatoid arthritis. Journal of Interferon and Cytokine Research 31: 745–751.

von Boehmer H (1994) Positive selection of lymphocytes. Cell 76: 219–228.

Wolff MJ , Leung JM , Davenport M et al. (2010) Th17, Th22 and Treg cells are enriched in healthy human cecum. PLoS One 7(7): e41373.

Yaswen L , Kulkarni AB , Fredrickson T et al. (1996) Autoimmune manifestations in the transforming growth factor‐β1 knock‐out mouse. Blood 87: 1439–1445.

Yoshimura T , Takeda A , Hamano S et al. (2006) Two‐sided roles of IL‐27. Journal of Immunology 177: 5377–5385.

Further Reading

Alan R , Ezekowitz B and Hoffmann JA (2003) Innate Immunity. Totowa, NJ, USA: Humana Press.

Alberts B , Johnson A , Lewis J et al. (2002) Molecular Biology of the Cell, 4th edn. New York, USA: Garland Science.

Ibelgaufts H (2006) Cytokines & cells online pathfinder encyclopaedia (COPE).

Iwakura Y and Ishigame H (2006) The IL‐23/IL‐17 axis in inflammation. Journal of Clinical Investigation 116: 1218–1222.

Iwakura Y , Ishigame H , Saijo S and Nakae S (2011) Function specialization of interleukin‐17 family members. Immunity 34: 149–162.

Janeway CA Jr , Travers P , Walport M et al. (2001) Immunobiology: The immune System in Health and Disease, 5th edn. New York, USA: Garland Science.

Kaufmann SHE , Medzhitov R and Gordan S (2004) The Innate Immune Response to Infection. Washington DC, USA: ASM Press.

Katsikas PD , Schenberger SP and Pulendran B (eds) (2009 and 2013) Crossroads Between Innate and Adaptive Immunity III and IV. Advances in Experimental Medicine and Biology, vol. 780 and 785. Heidelberg, Germany: Springer.

Meager T (1998) The Molecular Biology of Cytokines. Chichester, UK: John Wiley.

Steinman RM and Hemmi H (2006) Dendritic cells: translating innate to adaptive immunity. Current Topics in Microbiology and Immunology 311: 17–58.

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Meager, Anthony, and Wadhwa, Meenu(Sep 2013) An Overview of Cytokine Regulation of Inflammation and Immunity. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024658]