Cytokines in Immune Response and Disorders: Cytokines and Soluble Inhibitors

Soohyun Kim

doi:10.53941/jiim.2025.100004

Abstract

Over a long period of time, animals have built defense mechanisms to block external intruders through a complex evolutionary process. The structure created at the center is called the immune system. In animals with a vascular system, immune cells circulating in the blood perform most of the role. Cytokines are substances that direct immune function and are not only produced by immune cells but also secreted by non-immune cells, contributing to the proliferation and differentiation of blood cells. Most blood cells are red blood cells that supply oxygen in the body, and a small number of white blood cells (WBC) perform immune functions. Even under normal circumstances, mammalian WBC are produced in the bone marrow, differentiate into various immune cells, and proliferate under the stimulation of cytokines. However, when infected with external pathogens, viruses, bacteria, fungi, and parasites, cytokines are produced exponentially and temporarily induce proliferation and differentiation of immune cells defending the host from pathogens. Once all pathogens are destroyed by immune cells, excessive cytokine activity is downregulated by soluble antagonists, such as cytokine binding proteins and ligands, but which have receptor antagonist properties. In this review, we will discuss the roles of cytokines, which are immune enhancers, and soluble cytokine binding proteins, which are immunosuppressants, and various autoimmune diseases that arf44ise from immune imbalance.

References

1.
Sehgal, M.; Ladd, H.J.; Totapally, B. Trends in Epidemiology and Microbiology of Severe Sepsis and Septic Shock in Children. Hosp. Pediatr. 2020, 10, 1021–1030.
2.
Iwasaki, A.; Medzhitov, R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 2015, 16, 343–353.
3.
Vivier, E.; Malissen, B. Innate and adaptive immunity: Specificities and signaling hierarchies revisited. Nat. Immunol. 2005, 6, 17–21.
4.
Kaminska, P.; Tempes, A.; Scholz, E.; Malik, A.R. Cytokines on the way to secretion. Cytokine Growth Factor. Rev. 2024, 79, 52–65.
5.
Van der Meide, P.H.; Schellekens, H. Cytokines and the immune response. Biotherapy 1996, 8, 243–249.
6.
Barnes, P.J. Th2 cytokines and asthma: An introduction. Respir. Res. 2001, 2, 64–65.
7.
Kalvakolanu, D.V. An introduction to the special issue on “cytokines and autoimmune diseases”. J. Interferon Cytokine Res. 2011, 31, 693–694.
8.
Kullberg, B.J.; van der Meer, J.W. Introduction: Cytokines in the biotherapy of infectious diseases. Biotherapy 1994, 7, 149–150.
9.
Ryffel, B. Pathology induced by inflammatory cytokines. Introd. Int. Rev. Exp. Pathol. 1993, 34, 3–6.
10.
Tovey, M.G. Introduction: Lessons Learnt from the Use of Cytokines and Cytokine Antagonists. J. Interferon Cytokine Res. 2014, 34, 921–922.
11.
Ward, N.L. Introduction to a special issue on Skin disease, immune response and cytokines. Cytokine 2015, 73, 309–310.
12.
Borden, E. Cytokines and monoclonal antibodies: An introduction of their current and future applications to cancer and other diseases. In Medical Section Proceedings; Med Sect Proc. 1992; pp. 51–62.
13.
Dinarello, C.A. Introduction to the interleukin-1 family of cytokines and receptors: Drivers of innate inflammation and acquired immunity. Immunol. Rev. 2018, 281, 5–7.
14.
Ghezzi, P. Cytokines: A pharmacologically-oriented introduction. Eur. Cytokine Netw. 1997, 8, 289–290.
15.
Metcalf, D. Polyfunctional cytokines: IL-6 and LIF. Introduction. Ciba Found. Symp. 1992, 167, 1–4.
16.
Kaser, A.; Novick, D.; Rubinstein, M.; Siegmund, B.; Enrich, B.; Koch, R.O.; Vogel, W.; Kim, S.H.; Dinarello, C.A.; Tilg, H. Interferon-alpha induces interleukin-18 binding protein in chronic hepatitis C patients. Clin. Exp. Immunol. 2002, 129, 332–338.
17.
Kim, S.; Yu, H.; Azam, T.; Dinarello, C.A. Interleukin-18 Binding Protein (IL-18BP): A Long Journey From Discovery to Clinical Application. Immune Netw. 2024, 24, e1.
18.
Kim, S.H.; Azam, T.; Novick, D.; Yoon, D.Y.; Reznikov, L.L.; Bufler, P.; Rubinstein, M.; Dinarello, C.A. Identification of amino acid residues critical for biological activity in human interleukin-18. J. Biol. Chem. 2002, 277, 10998–11003.
19.
Kim, S.H.; Eisenstein, M.; Reznikov, L.; Fantuzzi, G.; Novick, D.; Rubinstein, M.; Dinarello, C.A. Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc. Natl. Acad. Sci. USA 2000, 97, 1190–1195.
20.
Novick, D.; Engelmann, H.; Wallach, D.; Rubinstein, M. Soluble cytokine receptors are present in normal human urine. J. Exp. Med. 1989, 170, 1409–1414.
21.
Novick, D.; Kim, S.H.; Fantuzzi, G.; Reznikov, L.L.; Dinarello, C.A.; Rubinstein, M. Interleukin-18 binding protein: A novel modulator of the Th1 cytokine response. Immunity 1999, 10, 127–136.
22.
Park, S.Y.; Hisham, Y.; Shin, H.M.; Yeom, S.C.; Kim, S. Interleukin-18 Binding Protein in Immune Regulation and Autoimmune Diseases. Biomedicines 2022, 10, 1750.
23.
Megha, K.B.; Joseph, X.; Akhil, V.; Mohanan, P.V. Cascade of immune mechanism and consequences of inflammatory disorders. Phytomedicine 2021, 91, 153712.
24.
Ali, S.; Mann-Nuttel, R.; Schulze, A.; Richter, L.; Alferink, J.; Scheu, S. Sources of Type I Interferons in Infectious Immunity: Plasmacytoid Dendritic Cells Not Always in the Driver’s Seat. Front. Immunol. 2019, 10, 778.
25.
Emam, E.A.; Emam, M.; Shehata, A.E.; Emara, M. Impact of Schistosoma mansoni co-infection on serum profile of interferon-gamma, interleukin-4 and interleukin-10 in patients with chronic hepatitis C virus infection. Egypt. J. Immunol. 2006, 13, 33–40.
26.
Heirwegh, E.; MacLean, E.; He, J.; Kamhawi, S.; Sagan, S.M.; Olivier, M. Sandfly Fever Sicilian Virus-Leishmania major co-infection modulates innate inflammatory response favoring myeloid cell infections and skin hyperinflammation. PLoS Negl. Trop. Dis. 2021, 15, e0009638.
27.
Ma, Y.; Su, X.Z.; Lu, F. The Roles of Type I Interferon in Co-infections With Parasites and Viruses, Bacteria, or Other Parasites. Front. Immunol. 2020, 11, 1805.
28.
Chaplin, D.D. Overview of the immune response. J. Allergy Clin. Immunol. 2010, 125, S3–S23.
29.
Netea, M.G.; Dominguez-Andres, J.; Barreiro, L.B.; Chavakis, T.; Divangahi, M.; Fuchs, E.; Joosten, L.A.B.; van der Meer, J.W.M.; Mhlanga, M.M.; Mulder, W.J.M.; et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 2020, 20, 375–388.
30.
Verrall, A.J.; Schneider, M.; Alisjahbana, B.; Apriani, L.; van Laarhoven, A.; Koeken, V.; van Dorp, S.; Diadani, E.; Utama, F.; Hannaway, R.F.; et al. Early Clearance of Mycobacterium tuberculosis Is Associated With Increased Innate Immune Responses. J. Infect. Dis. 2020, 221, 1342–1350.
31.
Fajgenbaum, D.C.; June, C.H. Cytokine Storm. N. Engl. J. Med. 2020, 383, 2255–2273.
32.
Jung, S.M.; Kim, W.U. Targeted Immunotherapy for Autoimmune Disease. Immune Netw. 2022, 22, e9.
33.
Billmeier, U.; Dieterich, W.; Neurath, M.F.; Atreya, R. Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases. World J. Gastroenterol. 2016, 22, 9300–9313.
34.
Lee, J.U.; Shin, W.; Son, J.Y.; Yoo, K.Y.; Heo, Y.S. Molecular Basis for the Neutralization of Tumor Necrosis Factor alpha by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases. Int. J. Mol. Sci. 2017, 18, 228.
35.
Zhao, J.; Lu, Q.; Liu, Y.; Shi, Z.; Hu, L.; Zeng, Z.; Tu, Y.; Xiao, Z.; Xu, Q. Th17 Cells in Inflammatory Bowel Disease: Cytokines, Plasticity, and Therapies. J. Immunol. Res. 2021, 2021, 8816041.
36.
Kwak, A.; Lee, Y.; Kim, H.; Kim, S. Intracellular interleukin (IL)-1 family cytokine processing enzyme. Arch. Pharm. Res. 2016, 39, 1556–1564.
37.
Botsios, C. Safety of tumour necrosis factor and interleukin-1 blocking agents in rheumatic diseases. Autoimmun. Rev. 2005, 4, 162–170.
38.
Goldbach-Mansky, R. Blocking interleukin-1 in rheumatic diseases. Ann. N. Y. Acad. Sci. 2009, 1182, 111–123.
39.
van der Hilst, J.; Moutschen, M.; Messiaen, P.E.; Lauwerys, B.R.; Vanderschueren, S. Efficacy of anti-IL-1 treatment in familial Mediterranean fever: A systematic review of the literature. Biologics 2016, 10, 75–80.
40.
Alten, R. Tocilizumab: A novel humanized anti-interleukin 6 receptor antibody for the treatment of patients with rheumatoid arthritis. Ther. Adv. Musculoskelet. Dis. 2011, 3, 133–149.
41.
Mihara, M.; Ohsugi, Y.; Kishimoto, T. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, for treatment of rheumatoid arthritis. Open Access Rheumatol. 2011, 3, 19–29.
42.
Costache, D.O.; Feroiu, O.; Ghilencea, A.; Georgescu, M.; Caruntu, A.; Caruntu, C.; Tiplica, S.G.; Jinga, M.; Costache, R.S. Skin Inflammation Modulation via TNF-alpha, IL-17, and IL-12 Family Inhibitors Therapy and Cancer Control in Patients with Psoriasis. Int. J. Mol. Sci. 2022, 23, 5198.
43.
Napolitano, M.; di Vico, F.; Ruggiero, A.; Fabbrocini, G.; Patruno, C. The hidden sentinel of the skin: An overview on the role of interleukin-13 in atopic dermatitis. Front. Med. 2023, 10, 1165098.
44.
Walsh, G.M. Biologics targeting IL-5, IL-4 or IL-13 for the treatment of asthma—An update. Expert. Rev. Clin. Immunol. 2017, 13, 143–149.
45.
Bleecker, E.; Blaiss, M.; Jacob-Nara, J.; Huynh, L.; Duh, M.S.; Guo, T.; Ye, M.; Stanford, R.H.; Wang, Z.; Soler, X.; et al. Comparative effectiveness of dupilumab and omalizumab on asthma exacerbations and systemic corticosteroid prescriptions: Real-world US ADVANTAGE study. J. Allergy Clin. Immunol. 2024, 154, 1500–1510.
46.
Muller, S.; Maintz, L.; Bieber, T. Treatment of atopic dermatitis: Recently approved drugs and advanced clinical development programs. Allergy 2024, 79, 1501–1515.
47.
Konen, F.F.; Mohn, N.; Witte, T.; Schefzyk, M.; Wiestler, M.; Lovric, S.; Hufendiek, K.; Schwenkenbecher, P.; Suhs, K.W.; Friese, M.A.; et al. Treatment of autoimmunity: The impact of disease-modifying therapies in multiple sclerosis and comorbid autoimmune disorders. Autoimmun. Rev. 2023, 22, 103312.

Scilight Press

Author Information

Abstract

Graphical Abstract

Keywords

References

About Scilight

Journals

Publishing Policies

Contact Us