Anti-inflammatory Molecules: Immune System Mediators

  • B. C. Bhavya
  • Madathilkovilakath HaridasEmail author


Inflammation typifies the chief defensive mechanism against infection or injury. However, its obnoxious activation often elicits exaggerated immune response and the onset of clinically relevant detrimental responses. Suppression of inflammatory response by means of anti-inflammatory molecules is therefore weighed as a pivotal therapeutic solution to a wide range of diseases. The quest for newer and vital anti-inflammatory molecules has been considered as an active research vista for the development of potential drug candidates for a variety of pathological conditions. Inflammation and immune responses are inseparably linked in many instances, where the persisting inflammatory response serves as the key trigger for immune disorders. The immune system comprises immune cells and immunoglobulins, which are the major mediators of defensive response against obnoxious stimuli. Several anti-inflammatory molecules have been found to ameliorate immune reaction underlying many pathogenesis, via directly regulating production/function/activation of the prime components of the immune system and limit tissue damage. This chapter provides an insight into the ability of such anti-inflammatory molecules which target components of the immune system. The interplay of adaptive immunity and inflammatory mechanism in terms of chronic inflammatory disease pathogenesis is critically evaluated and demonstrated. An effort has been made to explain how this approach of inhibiting inflammatory targets qualifies as a potent therapeutic solution for immune disorders and transplant rejection. The emphasis is on identifying plausible anti-inflammatory agents targeting immune system mediators as a logical strategy for novel and efficient therapeutic interventions.


Inflammation Immune response Immune system mediators Anti-inflammatory agents Chronic inflammatory diseases 


  1. Abramson S, Weissmann G (1981) The release of inflammatory mediators from neutrophils. Ric Clin Lab 11(2):91–99Google Scholar
  2. Arend WP (2002) The mode of action of cytokine inhibitors. J Rheumatol 65:16–21Google Scholar
  3. Ballanti E, Perricone C, di Muzio G, Kroegler B, Chimenti MS, Graceffa D, Perricone R (2011) Role of the complement system in rheumatoid arthritis and psoriatic arthritis: relationship with anti-TNF inhibitors. Autoimmun Rev 10:617–623CrossRefPubMedGoogle Scholar
  4. Banyer JL, Hamilton NH, Ramshaw IA, Ramsay AJ (2000) Cytokines in innate and adaptive immunity. Rev Immunogenet 2:359–373PubMedGoogle Scholar
  5. Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G (2007) Nonallergic angiodema: role of Bradykinin. Allergy 62(8):842–856Google Scholar
  6. Bell SJ, Kamm MA (2000) Review article: the clinical role of anti-TNFalpha antibody treatment in Crohn’s disease. Aliment Pharmacol Ther 14:501–514CrossRefPubMedGoogle Scholar
  7. Camp NJ, Cox A, di Giovine FS, McCabe D, Rich W, Duff GW (2005) Evidence of a pharmacogenomic response to interleukin-l receptor antagonist in rheumatoid arthritis. Genes Immun 6:467–471CrossRefPubMedGoogle Scholar
  8. Capetti AF, Pocaterra D, Zucchi P, Carenzi L, Rizzardini G (2010) Anti-inflammatory effect of maraviroc in an HIV-infected patient with concomitant myositis: a case report. J Inter Ass Phys AIDS Care (Chicago) 9:201–202Google Scholar
  9. Castro Villegas Mdel C, Escudero Contreras A, Miranda Garcia MD, Collantes Estevez E (2012) How to optimize the anti-TNF alpha therapy in spondylitis? Reumatologia Clinica 8(1):S26–S31CrossRefPubMedGoogle Scholar
  10. Chagnon M, Gentile J, Gladu M, Sirois P (1985) The mechanism of action of leukotrienes A4, C4 and D4 on human lung parenchyma in vitro. Lung 163:55–62CrossRefPubMedGoogle Scholar
  11. Clark W, Jobanputra P, Barton P, Burls A (2004) The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis. Health Tech Assess 8:iii–iv, ix–x, 1–105Google Scholar
  12. Cook EB (2004) Tear cytokines in acute and chronic ocular allergic inflammation. Curr Opin Allergy Clin Immunol 4:441–445CrossRefPubMedGoogle Scholar
  13. D’Ambrosio D, Panina-Bordignon P, Sinigaglia F (2003) Chemokine receptors in inflammation: an overview. J Immunol Methods 273:3–13CrossRefPubMedGoogle Scholar
  14. de La Mata LJ, Gonzalez Crespo R, Maese Manzano J (2007) Treatment of rheumatoid arthritis with anakinra: a systematic review. Reumatol Clinica 3:153–158CrossRefGoogle Scholar
  15. Donnelly LE, Barnes PJ (2006) Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease. Trends Pharmacol Sci 27:546–553CrossRefPubMedGoogle Scholar
  16. Du Buske LM (1996) Clinical comparison of histamine H1-receptor antagonist drugs. J Allergy Clin Immunol 98:S307–S318CrossRefPubMedGoogle Scholar
  17. Ehrnthaller C, Ignatius A, Gebhard F, Huber-Lang M (2011) New insights of an old defense system: structure, function, and clinical relevance of the complement system. Mol Med 17:317–329CrossRefPubMedGoogle Scholar
  18. El-Asrar AM (2012) Role of inflammation in the pathogenesis of diabetic retinopathy. Middle East Afr J Ophthal 19:70–74CrossRefGoogle Scholar
  19. Elices MJ (2002) BX-471 Berlex. Curr Opin Investig Drugs 3:865–869Google Scholar
  20. Feghali CA, Wright TM (1997) Cytokines in acute and chronic inflammation. Front Biosci 2:d12–d26CrossRefPubMedGoogle Scholar
  21. Feldmann M, Maini RN (2001) Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 19:163–196CrossRefPubMedGoogle Scholar
  22. Francisci D, Falcinelli E, Baroncelli S, Petito E, Cecchini E, Weimer LE, Floridia M, Gresele P, Baldelli F (2014) Potential anti-inflammatory effects of maraviroc in HIV-positive patients: a pilot study of inflammation, endothelial dysfunction, and coagulation markers. Scand J Infect Dis 46:466–470CrossRefPubMedGoogle Scholar
  23. Furst R, Zundorf I (2014) Plant-derived anti-inflammatory compounds: hopes and disappointments regarding the translation of preclinical knowledge into clinical progress. Mediat Inflamm 2014:146832CrossRefGoogle Scholar
  24. Garcia-Marcos L, Schuster A (2001) Antileukotrienes in asthma: present situation. Expert Opin Pharmacother 2:441–466CrossRefPubMedGoogle Scholar
  25. Greene ER, Huang S, Serhan CN, Panigrahy D (2011) Regulation of inflammation in cancer by eicosanoids. Prostaglandins Other Lipid Mediat 96:27–36CrossRefPubMedCentralPubMedGoogle Scholar
  26. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899CrossRefPubMedCentralPubMedGoogle Scholar
  27. Hampel U, Sesselmann S, Iserovich P, Sel S, Paulsen F, Sack R (2013) Chemokine and cytokine levels in osteoarthritis and rheumatoid arthritis synovial fluid. J Immunol Methods 396:134–139CrossRefPubMedGoogle Scholar
  28. Handa P, Kowdley KV (2013) Chemokines: potent mediators of hepatic inflammation and fibrosis in chronic liver diseases. Ann Hepatol 13:152–154PubMedGoogle Scholar
  29. Harter WG, Albrect H, Brady K, Caprathe B, Dunbar J, Gilmore J, Hays S, Kostlan CR, Lunney B, Walker N (2004) The design and synthesis of sulfonamides as caspase-1 inhibitors. Bioorg Med Chem Lett 14:809–812CrossRefPubMedGoogle Scholar
  30. Haspel RL, Hillmen P (2008) Which patients with paroxysmal nocturnal hemoglobinuria (PNH) should be treated with eculizumab? ASH evidence-based review 2008. Hematology Am Soc Hematol Educ Program 2008:35Google Scholar
  31. Hedqvist P, Dahlen SE, Palmertz U (1985) Leukotrienes as mediators of airway anaphylaxis. Adv Prostaglandin Thromboxane Leukot Res 15:345–348PubMedGoogle Scholar
  32. Holers VM (2016) Targeting mechanisms at sites of complement activation for imaging and therapy. Immunobiology 221(6):726–732CrossRefPubMedGoogle Scholar
  33. Jablonowski JA, Carruthers NI, Thurmond RL (2004) The histamine H4 receptor and potential therapeutic uses for H4 ligands. Mini-Rev Med Chem 4:993–1000CrossRefPubMedGoogle Scholar
  34. Jang MH, Seoh JY, Miyasaka M (2006) Cytokines, chemokines, and their receptors: targets for immunomodulation. Conference report: international cytokine society conference 2005. J Leukoc Biol 80:217–219CrossRefPubMedGoogle Scholar
  35. Kadioglu A, Sheldon P (1996) Adhesion of rheumatoid lymphocytes to mucosal endothelium: the gut revisited. Br J Rheumatol 35:218–225CrossRefPubMedGoogle Scholar
  36. Keating GM (2013) Eculizumab: a review of its use in atypical haemolytic uraemic syndrome. Drugs 73:2053–2066CrossRefPubMedGoogle Scholar
  37. Kemp JP (2003) Recent advances in the management of asthma using leukotriene modifiers. Am J Respir Med 2:139–156CrossRefPubMedGoogle Scholar
  38. Khanapure SP, Garvey DS, Janero DR, Letts LG (2007) Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers. Curr Top Med Chem 7:311–340CrossRefPubMedGoogle Scholar
  39. Kirschfink M (2001) Targeting complement in therapy. Immunol Rev 180:177–189CrossRefPubMedGoogle Scholar
  40. Kiss R, Keseru GM (2012) Histamine H4 receptor ligands and their potential therapeutic applications: an update. Expert Opin Ther Pat 22:205–221CrossRefPubMedGoogle Scholar
  41. Kiss R, Keseru GM (2014) Novel histamine H4 receptor ligands and their potential therapeutic applications: an update. Expert Opin Ther Pat 24:1185–1197CrossRefPubMedGoogle Scholar
  42. Krystal AD, Richelson E, Roth T (2013) Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications. Sleep Med Rev 17:263–272CrossRefPubMedGoogle Scholar
  43. Lam BK, Lee CY, Wong PY (1988) Phospholipase A2 (PLA2) releases lipoxins and leukotrienes from endogenous sources. Ann N Y Acad Sci 524:27–34CrossRefPubMedGoogle Scholar
  44. Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, Braun D, Banerjee S (2012) Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 366:1190–1199CrossRefPubMedGoogle Scholar
  45. Martinel Lamas DJ, Rivera ES, Medina VA (2015) Histamine H4 receptor: insights into a potential therapeutic target in breast cancer. Front Biosci (Scholar Edition) 7:1–9CrossRefGoogle Scholar
  46. Martorana G, Casa A, Oliva L, Orlando A, Cottone M (2001) Treatment with chimeric monoclonal antitumor necrosis factor (infliximab) of patients with active steroid-dependent/resistant Crohn’s disease and fistulas. Recenti Prog Med 92:451–455PubMedGoogle Scholar
  47. Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428–435CrossRefPubMedGoogle Scholar
  48. Milligan CE, Prevette D, Yaginuma H, Homma S, Cardwell C, Fritz LC, Tomaselli KJ, Oppenheim RW, Schwartz LM (1995) Peptide inhibitors of the ICE protease family arrest programmed cell death of motoneurons in vivo and in vitro. Neuron 15:385–393CrossRefPubMedGoogle Scholar
  49. Mollnes TE, Kirschfink M (2006) Strategies of therapeutic complement inhibition. Mol Immunol 43:107–121CrossRefPubMedGoogle Scholar
  50. Montuschi P, Mondino C, Koch P, Barnes PJ, Ciabattoni G (2006) Effects of a leukotriene receptor antagonist on exhaled leukotriene E4 and prostanoids in children with asthma. J Allergy Clin Immunol 118:347–353CrossRefPubMedGoogle Scholar
  51. Morton AC, Arnold ND, Gunn J, Varcoe R, Francis SE, Dower SK, Crossman DC (2005) Interleukin-1 receptor antagonist alters the response to vessel wall injury in a porcine coronary artery model. Cardiovasc Res 68:493–501CrossRefPubMedGoogle Scholar
  52. Moseley TA, Haudenschild DR, Rose L, Reddi AH (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14:155–174CrossRefPubMedGoogle Scholar
  53. Mosesson MW, Siebenlist KR, Meh DA (2001) The structure and biological features of fibrinogen and fibrin. Ann N Y Acad Sci 936:11–30Google Scholar
  54. Navab M, Gharavi N, Watson AD (2008) Inflammation and metabolic disorders. Curr Opin Clin Nutr Metab Care 11:459–464CrossRefPubMedGoogle Scholar
  55. Ni J, Shu YY, Zhu YN, Fu YF, Tang W, Zhong XG, Wang H, Yang YF, Ren J, Wang MW, Zuo JP (2007) COX-2 inhibitors ameliorate experimental autoimmune encephalomyelitis through modulating IFN-gamma and IL-10 production by inhibiting T-bet expression. J Neuroimmunol 186:94–103CrossRefPubMedGoogle Scholar
  56. Okamoto Y, Anan H, Nakai E, Morihira K, Yonetoku Y, Kurihara H, Sakashita H, Terai Y, Takeuchi M, Shibanuma T, Isomura Y (1999) Peptide based interleukin-1β-converting enzyme (ICE) inhibitors: synthesis, structure activity relationships and crystallographic study of the ICE-inhibitor complex. Chem Pharm Bull (Tokyo) 47:11–21CrossRefGoogle Scholar
  57. Owens T (2003) The enigma of multiple sclerosis: inflammation and neurodegeneration cause heterogeneous dysfunction and damage. Curr Opin Neurol 16:259–265CrossRefPubMedGoogle Scholar
  58. Parker CW (1982) Leukotrienes: their metabolism, structure, and role in allergic responses. Adv Prostaglandin Thromboxane Leukot Res 9:115–126PubMedGoogle Scholar
  59. Patel AM, Moreland LW (2010) Interleukin-6 inhibition for treatment of rheumatoid arthritis: a review of tocilizumab therapy. Drug Design Develop Ther 4:263–278CrossRefGoogle Scholar
  60. Perricone C, De Carolis C, Giacomelli R, Greco E, Cipriani P, Ballanti E, Novelli L, Perricone R (2011) Inhibition of the complement system by glutathione: molecular mechanisms and potential therapeutic implications. Int J Immunopathol Pharmacol 24:63–68CrossRefPubMedGoogle Scholar
  61. Petering H, Kohl J, Weyergraf A, Dulkys Y, Kimmig D, Smolarski R, Kapp A, Elsner J (2000) Characterization of synthetic C3a analog peptides on human eosinophils in comparison to the native complement component C3a. J Immunol 164:3783–3789CrossRefPubMedGoogle Scholar
  62. Piatti G, Ceriotti L, Cavallaro G, Ambrosetti U, Mantovani M, Pistone A, Centanni S (2003) Effects of zafirlukast on bronchial asthma and allergic rhinitis. Pharmacol Res 47:541–547CrossRefPubMedGoogle Scholar
  63. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJ (1999) Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 340:1398–1405CrossRefPubMedGoogle Scholar
  64. Proudfoot AE, Power CA, Schwarz MK (2010) Anti-chemokine small molecule drugs: a promising future? Expert Opin Investig Drugs 19:345–355CrossRefPubMedGoogle Scholar
  65. Randle JC, Harding MW, Ku G, Schonharting M, Kurrle R (2001) ICE/caspase-1 inhibitors as novel anti-inflammatory drugs. Expert Opin Investig Drugs 10:1207–1209CrossRefPubMedGoogle Scholar
  66. Rathbone J, Kaltenthaler E, Richards A, Tappenden P, Bessey A, Cantrell A (2013) A systematic review of eculizumab for atypical haemolytic uraemic syndrome (aHUS). BMJ Open 3:e003573CrossRefPubMedCentralPubMedGoogle Scholar
  67. Renné T, Schmaier AH, Nickel KF, Blombäck M, Maas C (2012) In vivo roles of factor XII. Blood 120(22):4296–4303. doi: 10.1182/blood-2012-07-292094
  68. Rickert M, Wang X, Boulanger MJ, Goriatcheva N, Garcia KC (2005) The structure of interleukin-2 complexed with its alpha receptor. Science 308:1477–1480CrossRefPubMedGoogle Scholar
  69. Rouzer CA, Marnett LJ (2009) Cyclooxygenases: structural and functional insights. J Lipid Res 50(Suppl):S29–S34PubMedCentralPubMedGoogle Scholar
  70. Russo RC, Garcia CC, Teixeira MM, Amaral FA (2014) The CXCL8/IL-8 chemokine family and its receptors in inflammatory diseases. Expert Rev Clin Immunol 10:593–619CrossRefPubMedGoogle Scholar
  71. Sarma JV, Ward PA (2011) The complement system. Cell Tissue Res 343:227–235CrossRefPubMedGoogle Scholar
  72. Schreiber S (2007) Crohn’s disease–infliximab, adalimumab and certolizumab-pegol: clinical value of anti-TNF-alpha treatment. Dtsch Med Wochenschr 132:1770–1774CrossRefPubMedGoogle Scholar
  73. Scully CC, Blakeney JS, Singh R, Hoang HN, Abbenante G, Reid RC, Fairlie DP (2010) Selective hexapeptide agonists and antagonists for human complement C3a receptor. J Med Chem 53:4938–4948CrossRefPubMedGoogle Scholar
  74. Semple G, Ashworth DM, Batt AR, Baxter AJ, Benzies DW, Elliot LH, Evans DM, Franklin RJ, Hudson P, Jenkins PD et al (1998) Peptidomimetic aminomethylene ketone inhibitors of interleukin-1 beta-converting enzyme (ICE). Bioorg Med Chem Lett 8:959–964CrossRefPubMedGoogle Scholar
  75. Shahripour AB, Plummer MS, Lunney EA, Albrecht HP, Hays SJ, Kostlan CR, Sawyer TK, Walker NP, Brady KD, Allen HJ, Talanian RV, Wong WW, Humblet C (2002) Structure-based design of nonpeptide inhibitors of interleukin-1beta converting enzyme (ICE, caspase-1). Bioorg Med Chem 10:31–40CrossRefPubMedGoogle Scholar
  76. Smith LS, Nelson M, Dolder CR (2010) Certolizumab pegol: a TNF-{alpha} antagonist for the treatment of moderate-to-severe Crohn’s disease. Ann Pharmacother 44:333–342CrossRefPubMedGoogle Scholar
  77. Somm E, Cettour-Rose P, Asensio C, Charollais A, Klein M, Theander-Carrillo C, Juge-Aubry CE, Dayer JM, Nicklin MJ, Meda P, Rohner-Jeanrenaud F, Meier CA (2006) Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents. Diabetologia 49:387–393CrossRefPubMedGoogle Scholar
  78. Soper DL, Sheville JX, O’Neil SV, Wang Y, Laufersweiler MC, Oppong KA, Wos JA, Ellis CD, Baize MW, Chen JJ, Fancher AN, Lu W, Suchanek MK, Wang RL, Schwecke WP, Cruze CA, Buchalova M, Belkin M, Wireko F, Ritter A, De B, Wang D, Demuth TP Jr (2006) Synthesis and evaluation of novel 8,5-fused bicyclic peptidomimetic compounds as interleukin-1beta converting enzyme (ICE) inhibitors. Bioorg Med Chem 14:7880–7892CrossRefPubMedGoogle Scholar
  79. Soter NA, Austen KF (1976) The diversity of mast cell-derived mediators: implications for acute, subacute, and chronic cutaneous inflammatory disorders. J Invest Dermatol 67(3):313–319Google Scholar
  80. Tesch H, König W (1979) Origin and biological role of lipid mediators during inflammation (author’s transl). Immun Infekt 7(5):157–164Google Scholar
  81. Trivella DB, Ferreira-Junior JR, Dumoutier L, Renauld JC, Polikarpov I (2010) Structure and function of interleukin-22 and other members of the interleukin-10 family. Cell Mol Life Sci 67:2909–2935CrossRefPubMedGoogle Scholar
  82. Van Snick J (1990) Interleukin-6: an overview. Annu Rev Immunol 8:253–278CrossRefPubMedGoogle Scholar
  83. Vezzani A, Balosso S, Maroso M, Zardoni D, Noe F, Ravizza T (2010) ICE/caspase 1 inhibitors and IL-1beta receptor antagonists as potential therapeutics in epilepsy. Curr Opin Investig Drugs 11:43–50PubMedGoogle Scholar
  84. Wagner G, Laufer S (2006) Small molecular anti-cytokine agents. Med Res Rev 26:1–62CrossRefPubMedGoogle Scholar
  85. Wang YS, Zhang Y, Liang H (2010) Role of microRNAs in diabetes and diabetes-associated complications. Sheng Li Ke Xue Jin Zhan 41:133–136PubMedGoogle Scholar
  86. Waugh J, Perry CM (2005) Anakinra: a review of its use in the management of rheumatoid arthritis. BioDrugs 19:189–202CrossRefPubMedGoogle Scholar
  87. Wu Y, Tai CL, Wei H, He F, Wang Y, Zhao Y, Chen HD (2008) Protective effects of cyclooxygenase-2 inhibitors on narrow-band ultraviolet B-irradiated epidermal Ia+ Langerhans cells and thy-1+ dendritic epidermal T cells in mice. Photochem Photobiol 84:484–488CrossRefPubMedGoogle Scholar
  88. Zhang L, Bertucci AM, Smith KA, Xu L, Datta SK (2007) Hyperexpression of cyclooxygenase 2 in the lupus immune system and effect of cyclooxygenase 2 inhibitor diet therapy in a murine model of systemic lupus erythematosus. Arthritis Rheum 56:4132–4141CrossRefPubMedGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Inter University Centre for Bioscience, Department of Biotechnology and MicrobiologyKannur UniversityKannurIndia

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