Serum Levels of Interleukin-36 Alpha and Interleukin-36 Receptor Antagonist In Behcet’s Syndrome

Abstract

Background Behcet’s syndrome (BS) is a systemic vasculitic disorder. This study aimed to investigate the levels of serum IL-36α and IL-36Ra in patients with BS.

Material and Methods A total of 80 subjects (60 BS patients and 20 healthy controls [HC]) were included.

Results The median IL-36α level was 0.11 ng/ml in the BS group and 0.09 ng/ml in the HC group (p=0.058). The mean IL-36Ra level was 13.62 pg/ml in the BS group and 13.26 pg/ml in the HC group (p=0.348). Serum IL-36Ra levels of the active group were significantly higher (p=0.037). Patients with oral ulcers and central nervous system involvement had higher serum IL36Ra levels. In the BS group, a positive correlation was found between serum IL-36Ra and CRP. In a multivariate analysis, the IL-36Ra level (OR=1.067; 95% CI=1.001–1.137; p=0.045) was independently associated with disease activity.

Conclusion According to these findings, it is not clear whether such a slight difference is clinically significant, but they suggest that the IL-36 cytokine family may play a role in the course of the disease.

Zusammenfassung

Hintergrund Das Behcet-Syndrom (BS) ist eine Form der systemischen Vaskulitiden. Ziel dieser Studie war es, die Serumspiegel von IL-36α und IL36Ra bei Patienten mit BS zu untersuchen.

Material und Methoden Insgesamt 80 Probanden (60 BS-Patienten und 20 gesunde Kontrollpersonen [KP]) wurden in die Studie eingeschlossen.

Ergebnisse Der mittlere IL-36α-Spiegel betrug im BS 0,11 ng/ml und im KP 0.09 ng/ml (p=0,058). Der mittlere IL-36Ra-Spiegel betrug 13,62 pg/ml im BS und 13,26 pg/ml im KP (p=0,348). Der IL-36Ra Serumspiegel der aktiven Gruppe waren signifikant höher (p=0,037). Patienten mit oralen Geschwüren und Beteiligung des zentralen Nervensystems hatten höhere IL-36Ra-Serumspiegel. In der BS Gruppe wurde eine positive Korrelation zwischen IL-36Ra und CRP im Serum gefunden. In der multivariaten Analyse war der IL-36Ra-Spiegel (OR=1067; 95% CI=1001–1137; p=0045) unabhängig mit der Krankheitsaktivität assoziiert.

Schlussfolgerung Nach diesen Erkenntnissen ist nicht klar, ob ein derart geringfügiger Unterschied eine klinische Bedeutung hat. Die Daten legen jedoch nahe, dass die IL-36-Zytokinfamilie möglicherweise eine Rolle im Krankheitsverlauf spielt.

Key words

Interleukin-36 - Immunologie - Pathogenesis - Vasculitis - Behcet’s syndrome

Schlüsselwörter

Interleukin-36 - Studienlage - Pathogenese - Vaskulitis - Behcet-Syndrom

• References

• 1 Alpsoy E. Behcet’s disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions. J Dermatol 2016; 43: 620-632
• 2 Zeidan MJ, Saadoun D, Garrido M. et al. Behçet’s disease physiopathology: a contemporary review. Autoimmunity Highlights 2016; 7: 4
• 3 Zhou Z, Chen S, Shen N. et al. Cytokines and Behcet’s disease. Autoimmunity reviews 2012; 11: 699-704
• 4 de Chambrun MP, Wechsler B, Geri G. et al. New insights into the pathogenesis of Behcet’s disease. Autoimmunity reviews 2012; 11: 687-698
• 5 Taylor SL, Renshaw BR, Garka KE. et al. Genomic organization of the interleukin-1 locus. Genomics 2002; 79: 726-733
• 6 Gabay C, Towne JE. Regulation and function of interleukin-36 cytokines in homeostasis and pathological conditions. Journal of leukocyte biology 2015; 97: 645-652
• 7 Foster AM, Baliwag J, Chen CS. et al. IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin. The Journal of Immunology 2014; 192: 6053-6061
• 8 Mutamba S, Allison A, Mahida Y. et al. Expression of IL-1Rrp2 by human myelomonocytic cells is unique to DCs and facilitates DC maturation by IL-1F8 and IL-1F9. European journal of immunology 2012; 42: 607-617
• 9 Ciccia F, Accardo-Palumbo A, Alessandro R. et al. Interleukin-36α axis is modulated in patients with primary Sjögren’s syndrome. Clinical & Experimental Immunology 2015; 181: 230-238
• 10 Gresnigt MS, van de Veerdonk FL. Biology of IL-36 cytokines and their role in disease. In: Seminars in immunology. Elsevier; 2013: 458-465
• 11 Walsh PT, Fallon PG. The emergence of the IL-36 cytokine family as novel targets for inflammatory diseases. Ann N Y Acad Sci 2018; 1417: 23-34
• 12 Marrakchi S, Guigue P, Renshaw BR. et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011; 365: 620-628
• 13 Cerci P, Altiner S, Inal A. et al. Investigating the role of IL-33 in the pathogenesis of Behcet’s Disease. Acta Clin Belg 2017; 72: 434-438
• 14 Lopalco G, Cantarini L, Vitale A. et al. Interleukin-1 as a common denominator from autoinflammatory to autoimmune disorders: premises, perils, and perspectives. Mediators of inflammation 2015; 2015
• 15 Ozguclu S, Duman T, Ates FSO. et al. Serum interleukin-37 level and interleukin-37 gene polymorphism in patients with Behcet disease. Clinical rheumatology 2019; 38: 495-502
• 16 Hahn M, Frey S, Hueber AJ. The novel interleukin-1 cytokine family members in inflammatory diseases. Current opinion in rheumatology 2017; 29: 208-213
• 17 Chu M, Wong CK, Cai Z. et al. Elevated expression and pro-inflammatory activity of IL-36 in patients with systemic lupus erythematosus. Molecules 2015; 20: 19588-19604
• 18 Cho S, Kim J, Cho SB. et al. Immunopathogenic characterization of cutaneous inflammation in Behcet’s disease. Journal of the European Academy of Dermatology and Venereology : JEADV 2014; 28: 51-57
• 19 Bassoy EY, Towne JE, Gabay C. Regulation and function of interleukin-36 cytokines. Immunol Rev 2018; 281: 169-178
• 20 Boutet MA, Nerviani A, Pitzalis C. IL-36, IL-37, and IL-38 Cytokines in Skin and Joint Inflammation: A Comprehensive Review of Their Therapeutic Potential. Int J Mol Sci 2019; 20
• 21 Zhou L, Todorovic V. Interleukin-36: Structure, Signaling and Function. Adv Exp Med Biol 2020;
• 22 Bonekamp N, Caorsi R, Viglizzo GM. et al. High-dose ustekinumab for severe childhood deficiency of interleukin-36 receptor antagonist (DITRA). Ann Rheum Dis 2018; 77: 1241-1243
• 23 Gomez-Garcia F, Sanz-Cabanillas JL, Viguera-Guerra I. et al. Scoping Review on Use of Drugs Targeting Interleukin 1 Pathway in DIRA and DITRA. Dermatol Ther (Heidelb) 2018; 8: 539-556
• 24 Hospach T, Glowatzki F, Blankenburg F. et al. Scoping review of biological treatment of deficiency of interleukin-36 receptor antagonist (DITRA) in children and adolescents. Pediatr Rheumatol Online J 2019; 17: 37
• 25 Buhl AL, Wenzel J. Interleukin-36 in Infectious and Inflammatory Skin Diseases. Front Immunol 2019; 10: 1162
• 26 Johnston A, Xing X, Guzman AM. et al. IL-1F5,-F6,-F8, and-F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression. The Journal of Immunology 2011; 186: 2613-2622
• 27 Frey S, Derer A, Messbacher M-E. et al. The novel cytokine interleukin-36α is expressed in psoriatic and rheumatoid arthritis synovium. Annals of the rheumatic diseases 2013; 72: 1569-1574
• 28 Boutet MA, Bart G, Penhoat M. et al. Distinct expression of interleukin (IL)-36alpha, beta and gamma, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn’s disease. Clin Exp Immunol 2016; 184: 159-173
• 29 Magne D, Palmer G, Barton JL. et al. The new IL-1 family member IL-1F8 stimulates production of inflammatory mediators by synovial fibroblasts and articular chondrocytes. Arthritis research & therapy 2006; 8: R80
• 30 Boutet MA, Nerviani A, Lliso-Ribera G. et al. Interleukin-36 family dysregulation drives joint inflammation and therapy response in psoriatic arthritis. Rheumatology (Oxford) 2020; 59: 828-838
• 31 Derer A, Groetsch B, Harre U. et al. Blockade of IL-36 receptor signaling does not prevent from TNF-induced arthritis. PloS one 2014; 9
• 32 Dietrich D, Gabay C. Inflammation: IL-36 has proinflammatory effects in skin but not in joints. Nature Reviews Rheumatology 2014; 10: 639
• 33 Berglöf E, Andre R, Renshaw BR. et al. IL-1Rrp2 expression and IL-1F9 (IL-1H1) actions in brain cells. Journal of neuroimmunology 2003; 139: 36-43
• 34 Karumbaiah L, Norman SE, Rajan NB. et al. The upregulation of specific interleukin (IL) receptor antagonists and paradoxical enhancement of neuronal apoptosis due to electrode induced strain and brain micromotion. Biomaterials 2012; 33: 5983-5996
• 35 Nishida A, Hidaka K, Kanda T. et al. Increased Expression of Interleukin-36, a Member of the Interleukin-1 Cytokine Family, in Inflammatory Bowel Disease. Inflammatory bowel diseases 2016; 22: 303-314
• 36 Scheibe K, Kersten C, Schmied A. et al. Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice With Chronic Intestinal Inflammation. Gastroenterology 2019; 156: 1082-1097 e1011
• 37 Floris A, Espinosa G, Serpa Pinto L. et al. Discordance between patient and physician global assessment of disease activity in Behcet’s syndrome: a multicenter study cohort. Arthritis Res Ther 2020; 22: 278