Inflammatory Mediators

Abstract

Cytokines and chemokines are soluble inflammatory mediators that are naturally produced during an inflammatory response. The type of immune response (pro‐ or anti‐inflammatory, cell mediated or humoral) elicited by these molecules largely depends on the initial cytokines released in response to bodily injury or pathogen invasion. The characteristic signs of inflammation: redness, swelling, heat and pain are the result of coordinated, intricate signalling responses by these soluble mediators that primarily facilitate cellular infiltration to the site of infection. The nature of the immune response is further complicated by the fact that several cytokines can promote both pro‐ and anti‐inflammatory responses. Although cytokines and chemokines are often effective at resolving inflammation, aberrant cytokine and chemokine signalling have been shown to contribute to many autoimmune diseases.

Key Concepts

  • Fine‐tuned immune signalling is critical for resolution of potentially harmful stimuli.
  • Inflammatory mediators are the molecules responsible for immunological homeostasis.
  • Cytokines and chemokines link the innate and adaptive immune systems.
  • Inflammatory mediators regulate physiological processes distinct from the immune system.
  • Cytokines and chemokines are powerful signalling proteins.
  • Arachidoic acid is synthesised into prostaglandins and leukotrienes.
  • Activation of the complement system yields anaphylatoxin production.

Keywords: inflammation; cytokine; chemokine; interleukin; macrophage activation; cellular infiltration; neutrophil; leukotrienes; prostaglandins; complement

Figure 1. Overview of the primary effector cells and their functions that contribute to inflammation.
Figure 2. Naïve CD4+ T helper (TH) cell differentiation into distinct effector subsets. Naïve CD4+ T cells are activated by dendritic cells within the lymph node. The TH subset is determined by the cytokine milieu in the lymph node during antigen presentation.
close

References

Bachelerie F, Graham GJ, Locati M, et al. (2014) New nomenclature for atypical chemokine receptors. Nature Immunology 15 (3): 207–208.

Barnes PJ (1990) Reactive oxygen species and airway inflammation. Free Radical Biology and Medicine 9 (3): 235–243.

Bazan JF, Bacon KB, Hardiman G, et al. (1997) A new class of membrane‐bound chemokine with a CX3C motif. Nature 385 (6617): 640–644.

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.

Billiau A and Matthys P (2009) Interferon‐gamma: a historical perspective. Cytokine Growth Factor Reviews 20: 97–113.

Bohlson SS, O'Conner SD, Hulsebus HJ, Ho M and Fraser DA (2014) Complement, C1q, and C1q‐related molecules regulate macrophage polarization. Frontiers in Immunology 5.

Breyer RM, Bagdassarian CK, Myers SA and Breyer MD (2001) Prostanoid receptors: subtypes and signaling 1. Annual Review of Pharmacology and Toxicology 41 (1): 661–690.

Chen CJ, Kono H, Golenbock D, Reed G, et al. (2007) Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nature Medicine 13: 851–856.

Ding L, Linsley PS, Huang LY, Germain RN and Shevach EM (1993) IL‐10 inhibits macrophage costimulatory activity by selectively inhibiting the up‐regulation of B7 expression. Journal of Immunology 151: 1224–1234.

Ehrnthaller C, Ignatius A, Gebhard F and Huber‐Lang M (2011) New insights of an old defense system: structure, function, and clinical relevance of the complement system. Molecular Medicine (Cambridge, Massachusetts) 17 (3–4): 317–329.

Fanning LB and Boyce JA (2013) Lipid mediators and allergic diseases. Annals of Allergy, Asthma & Immunology 111 (3): 155–162.

Garlanda C, Dinarello CA and Mantovani A (2013) The interleukin‐1 family: back to the future. Immunity 39: 1003–1018.

Hofmann S, Grasberger H, Jung P, et al. (2002) The tumour necrosis factor‐alpha induced vascular permeability is associated with a reduction of VD‐cadherin expression. European Journal of Medical Research 7: 171–176.

Ivanov II, McKenzie BS, Zhou L, et al. (2006) The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL‐17+ T helper cells. Cell 126: 1121–1133.

Kanaoka Y, Maekawa A and Austen KF (2013) Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand. The Journal of Biological Chemistry 288 (16): 10967–10972.

Kendall AC and Nicolaou A (2013) Bioactive lipid mediators in skin inflammation and immunity. Progress in Lipid Research 52 (1): 141–164.

Kuziel WA, Morgan SJ, Dawson TC, et al. (1997) Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proceedings of the National Academy of Sciences of the United States of America 94 (22): 12053–12058.

Lammermann T, Afonso PV, Angermann BR, et al. (2013) Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498 (7454): 371–375.

Mangan PR, Harrington LE, O'Quinn DB, Helms WS, et al. (2006) Transforming growth factor‐β induces development of the TH17 lineage. Nature 441: 231–234.

Mantovani A, Cassatella MA, Costantini C and Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nature Review Immunology 11: 519–531.

Marchi LF, Sesti‐Costa R, Ignacchiti MD, Chedraoui‐Silva S and Mantovani B (2014) In vitro activation of mouse neutrophils by recombinant human interferon‐gamma: increased phagocytosis and release of reactive oxygen species and pro‐inflammatory cytokines. International Immunopharmacology 18: 228–235.

Maurer M and von Stebut E (2004) Macrophage inflammatory protein‐1. The International Journal of Biochemistry & Cell Biology 36 (10): 1882–1886.

Meyer O (2009) Interferons and autoimmune disorders. Joint, Bone, Spine 76: 464–473.

Moelants EAV, Mortier A, Van Damme J and Proost P (2013) Regulation of TNF‐α with a focus on rheumatoid arthritis. Immunology and Cell Biology 91: 393–401.

Nathan C and Cunningham‐Bussel A (2013) Beyond oxidative stress: an immunologist's guide to reactive oxygen species. Nature Reviews Immunology 13 (5): 349–361.

Nicolaou A (2013) Eicosanoids in skin inflammation. Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA) 88 (1): 131–138.

Nomiyama H, Osada N and Yoshie O (2013) Systematic classification of vertebrate chemokines based on conserved synteny and evolutionary history. Genes to Cells 18 (1): 1–16.

Nonaka M (2014) Evolution of the Complement System, MACPF/CDC Proteins‐Agents of Defence, Attack and Invasion, pp. 31–43. Anonymous. London: Springer.

Rider P, Carmi Y, Guttman O, Braiman A, et al. (2011) IL‐1α and IL‐1β recruit different myeloid cells and promote different stages of sterile inflammation. Journal of Immunology 187: 4835–4843.

Roncarolo MG, Gregori S, Battaglia M, et al. (2006) Interleukin‐10‐secreting type 1 regulatory T cells in rodents and humans. Immunology Review 212: 28–50.

Russo RC, Garcia CC, Teixeira MM and Amaral FA (2014) The CXCL8/IL‐8 chemokine family and its receptors in inflammatory diseases. Expert Review of Clinical Immunology 10 (5): 593–619.

Santos JC, de Brito CA, Futata EA, et al. (2012) Up‐regulation of chemokine C‐C ligand 2 (CCL2) and C‐X‐C chemokine 8 (CXCL8) expression by monocytes in chronic idiopathic urticaria. Clinical & Experimental Immunology 167 (1): 129–136.

Schäfer B, Piliponsky AM, Oka T, et al. (2013) Mast cell anaphylatoxin receptor expression can enhance IgE‐dependent skin inflammation in mice. Journal of Allergy and Clinical Immunology 131 (2): 541–548.

Schauer C, Janko C, Munoz LE, et al. (2014) Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nature Medicine 20 (5): 511–517.

Schleimer RP, Sterbinsky SA, Kaiser J, et al. (1992) IL‐4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium. Association with expression of VCAM‐1. Journal of Immunology 148: 1086–1092.

Shachar I and Karin N (2013) The dual roles of inflammatory cytokines and chemokines in the regulation of autoimmune diseases and their clinical implications. Journal of Leukocyte Biology 93 (1): 51–61.

Smith WL and Langenbach R (2001) Why there are two cyclooxygenase isozymes. The Journal of Clinical Investigation 107 (12): 1491–1495.

Sone S, Yanagawa H, Nishioka Y, et al. (1992) Interleukin‐4 as a potent down‐regulator for human alveolar macrophages capable of producing tumour necrosis factor‐alpha and interleukin‐1. European Respiratory Journal 5: 174–181.

Steinke JW, Negri J, Enelow R, Baramki DF and Borish L (2006) Proinflammatory effects of IL‐4 antagonism. Journal of Allergy and Clinical Immunology 118: 756–758.

Tartaglia LA and Goeddel DV (1992) Two TNF receptors. Immunology Today 13: 151–153.

Travis MA and Sheppard D (2014) TGF‐β activation and function in immunity. Annual Review of Immunology 32: 51–82.

Vidal‐Vanaclocha F, Fantuzzi G, Mendoza L, Fuentes A, et al. (2000) IL‐18 regulates IL‐1β‐dependent hepatic melanoma metastasis via vascular cell adhesion molecule‐1. Proceedings of the National Academy of Sciences 97: 734–739.

Yang XO, Panopoulos AD, Nurieva R, et al. (2007) STAT3 regulates cytokine‐mediated generation of inflammatory helper T cells. Journal of Biological Chemistry 282: 9358–9363.

Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, et al. (1998) IL‐12 up‐regulates IL‐18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL‐18 for IFN‐γ production. Journal of Immunology 161: 3400–3407.

Yoshimura T, Matsushima K, Tanaka S, et al. (1987) Purification of a human monocyte‐derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines. Proceedings of the National Academy of Sciences of the United States of America 84 (24): 9233–9237.

Yost CC, Weyrich AS and Zimmerman GA (2010) The platelet activating factor (PAF) signaling cascade in systemic inflammatory responses. Biochimie 92 (6): 692–697.

Zhou L, Ivanov II, Spolski R, et al. (2007) IL‐6 programs TH‐17 cell differentiation by promoting sequential engagement of the IL‐21 and IL‐23 pathways. Nature Immunology 8: 967–974.

Further Reading

Commins SP, Borish L and Steinke JW (2010) Immunologic messenger molecules: cytokines, interferons, and chemokines. Journal of Allergy and Clinical Immunology 125: S53–S72.

Dinarello CA, Novick D, Kim S and Kaplanski G (2013) Interleukin‐18 and IL‐18 binding protein. Frontiers in Immunology 4: 1–10.

Griffith JW, Sokol CL and Luster AD (2014) Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annual Review of Immunology 32 (1): 659–702.

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

Mittal M, Siddiqui MR, Tran K, Reddy SP and Malik AB (2014) Reactive oxygen species in inflammation and tissue injury. Antioxidants & Redox Signaling 20 (7): 1126–1167.

Ng THS, Britton GJ, Hill EV, et al. (2013) Regulation of adaptive immunity; the role of interleukin‐10. Frontiers in Immunology 4: 1–13.

Pollard KM, Cauvi DM, Toomey CB, Morris KV and Kono DH (2013) Interferon‐γ and systemic autoimmunity. Discovery Medicine 16: 123–131.

Ricciotti E and FitzGerald GA (2011) Prostaglandins and inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology 31 (5): 986–1000.

Turner MD, Nedjai B, Hurst T and Pennington DJ (2014) Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochimica et Biophysica Acta (BBA) ‐ Molecular Cell Research 1843 (11): 2563–2582.

Zlotnik A and Yoshie O (2012) The chemokine superfamily revisited. Immunity 36 (5): 705–716.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Alvine, Travis D, Knopick, Peter L, Nilles, Matthew L, and Bradley, David S(Sep 2015) Inflammatory Mediators. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000945.pub2]