IL-18 in Autoinflammatory Diseases: Focus on Adult Onset Still Disease and Macrophages Activation Syndrome

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Jul 14

PMID 37446301

Authors

Chiara Baggio

Sara Bindoli

Irina Guidea

Andrea Doria

Francesca Oliviero

Paolo Sfriso

Affiliations

Soon will be listed here.

Abstract

Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine that is involved in various innate and adaptive immune processes related to infection, inflammation, and autoimmunity. Therefore, it is described as a key mediator of autoinflammatory diseases associated with the development of macrophage activation syndrome (MAS), including systemic juvenile idiopathic arthritis and adult-onset Still's disease. This review focuses on the role of IL-18 in inflammatory responses, placing emphasis on autoinflammatory diseases associated with chronic excess of serum IL-18, which correlate with clinical and biological signs of the disease. Therefore, it is useful for the diagnosis and monitoring of disease activity. Researchers are currently investigating IL-18's role as a therapeutic target for the treatment of inflammatory diseases. The inhibition of IL-18 signaling through recombinant human IL-18BP (IL-18 binding protein) seems to be an effective therapeutic strategy, though further studies are necessary to clarify its importance as a therapeutic target.

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References

Kuhns D, Fink D, Choi U, Sweeney C, Lau K, Priel D . Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency. Blood. 2016; 128(17):2135-2143. PMC: 5084607. DOI: 10.1182/blood-2016-03-706028. View

Puren A, Fantuzzi G, Gu Y, Su M, Dinarello C . Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNFalpha production from non-CD14+ human blood mononuclear cells. J Clin Invest. 1998; 101(3):711-21. PMC: 508617. DOI: 10.1172/JCI1379. View

Ogilvie E, Khan A, Hubank M, Kellam P, Woo P . Specific gene expression profiles in systemic juvenile idiopathic arthritis. Arthritis Rheum. 2007; 56(6):1954-65. DOI: 10.1002/art.22644. View

Netea M, Kullberg B, Verschueren I, van der Meer J . Interleukin-18 induces production of proinflammatory cytokines in mice: no intermediate role for the cytokines of the tumor necrosis factor family and interleukin-1beta. Eur J Immunol. 2000; 30(10):3057-60. DOI: 10.1002/1521-4141(200010)30:10<3057::AID-IMMU3057>3.0.CO;2-P. View

Banda N, Vondracek A, Kraus D, Dinarello C, Kim S, Bendele A . Mechanisms of inhibition of collagen-induced arthritis by murine IL-18 binding protein. J Immunol. 2003; 170(4):2100-5. DOI: 10.4049/jimmunol.170.4.2100. View

Girard-Guyonvarch C, Palomo J, Martin P, Rodriguez E, Troccaz S, Palmer G . Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice. Blood. 2018; 131(13):1430-1441. DOI: 10.1182/blood-2017-06-789552. View

Yasuda K, Nakanishi K, Tsutsui H . Interleukin-18 in Health and Disease. Int J Mol Sci. 2019; 20(3). PMC: 6387150. DOI: 10.3390/ijms20030649. View

Coppola S, Insalaco A, Zara E, Di Rocco M, Pires Marafon D, Spadaro F . Mutations at the C-terminus of CDC42 cause distinct hematopoietic and autoinflammatory disorders. J Allergy Clin Immunol. 2022; 150(1):223-228. DOI: 10.1016/j.jaci.2022.01.024. View

Canna S, de Jesus A, Gouni S, Brooks S, Marrero B, Liu Y . An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014; 46(10):1140-6. PMC: 4177369. DOI: 10.1038/ng.3089. View

10.

Kaplanski G . Interleukin-18: Biological properties and role in disease pathogenesis. Immunol Rev. 2017; 281(1):138-153. PMC: 7165732. DOI: 10.1111/imr.12616. View

11.

de Jager W, Vastert S, Beekman J, Wulffraat N, Kuis W, Coffer P . Defective phosphorylation of interleukin-18 receptor beta causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2009; 60(9):2782-93. DOI: 10.1002/art.24750. View

12.

Nakanishi K . Unique Action of Interleukin-18 on T Cells and Other Immune Cells. Front Immunol. 2018; 9:763. PMC: 5920033. DOI: 10.3389/fimmu.2018.00763. View

13.

Sumegi J, Barnes M, Nestheide S, Molleran-Lee S, Villanueva J, Zhang K . Gene expression profiling of peripheral blood mononuclear cells from children with active hemophagocytic lymphohistiocytosis. Blood. 2011; 117(15):e151-60. PMC: 3087540. DOI: 10.1182/blood-2010-08-300046. View

14.

Shibatomi K, Ida H, Yamasaki S, Nakashima T, Origuchi T, Kawakami A . A novel role for interleukin-18 in human natural killer cell death: high serum levels and low natural killer cell numbers in patients with systemic autoimmune diseases. Arthritis Rheum. 2001; 44(4):884-92. DOI: 10.1002/1529-0131(200104)44:4<884::AID-ANR145>3.0.CO;2-4. View

15.

Omoto Y, Yamanaka K, Tokime K, Kitano S, Kakeda M, Akeda T . Granzyme B is a novel interleukin-18 converting enzyme. J Dermatol Sci. 2010; 59(2):129-35. DOI: 10.1016/j.jdermsci.2010.05.004. View

16.

Nakahira M, Tomura M, Iwasaki M, Ahn H, Bian Y, Hamaoka T . An absolute requirement for STAT4 and a role for IFN-gamma as an amplifying factor in IL-12 induction of the functional IL-18 receptor complex. J Immunol. 2001; 167(3):1306-12. DOI: 10.4049/jimmunol.167.3.1306. View

17.

Shimizu M, Takei S, Mori M, Yachie A . Pathogenic roles and diagnostic utility of interleukin-18 in autoinflammatory diseases. Front Immunol. 2022; 13:951535. PMC: 9537046. DOI: 10.3389/fimmu.2022.951535. View

18.

Inoue N, Shimizu M, Tsunoda S, Kawano M, Matsumura M, Yachie A . Cytokine profile in adult-onset Still's disease: Comparison with systemic juvenile idiopathic arthritis. Clin Immunol. 2016; 169:8-13. DOI: 10.1016/j.clim.2016.05.010. View

19.

Mizuta M, Shimizu M, Inoue N, Ikawa Y, Nakagishi Y, Yasuoka R . Clinical significance of interleukin-18 for the diagnosis and prediction of disease course in systemic juvenile idiopathic arthritis. Rheumatology (Oxford). 2020; 60(5):2421-2426. DOI: 10.1093/rheumatology/keaa634. View

20.

Nold-Petry C, Lehrnbecher T, Jarisch A, Schwabe D, Pfeilschifter J, Muhl H . Failure of interferon gamma to induce the anti-inflammatory interleukin 18 binding protein in familial hemophagocytosis. PLoS One. 2010; 5(1):e8663. PMC: 2800185. DOI: 10.1371/journal.pone.0008663. View