Does IL33/Sst2 Pathway Play a Role in the Pathogenesis of Familial Mediterranean Fever?

Ayşe Bahar Keleşoğlu Dinçer

doi:10.4274/atfm.galenos.2022.12599

Araştırma Makalesi

Ailevi Akdeniz Ateşi Patogenezinde IL33/sST2 Yolağı Rol Oynamakta mıdır?

Yıl 2022, Cilt: 75 Sayı: 3, 406 - 412, 18.10.2022

Ayşe Bahar Keleşoğlu Dinçer

Öz

Amaç: İnterlökin-33 (IL-33); IL-1 süper ailesine ait yeni bir sitokindir. Ailevi Akdeniz Ateşi (FMF) patogenezinde yer alan IL-1β ile benzer yapısal ve sinyalizasyon yolağına sahiptir. Bu çalışmada, FMF hastalarının serumlarında IL-33 ve bunun reseptörü olan sST2 reseptör seviyelerinin ve hastalık aktivitesi ile ilişkisinin incelenmesi amaçlanmıştır.

Gereç ve Yöntem: Tek merkezli kesitsel olan bu çalışmaya, 18 yaş ve üzeri 76 FMF hastası ile yaş ve cinsiyet uyumlu 30 sağlıklı bireyler dahil edildi. Hastalık aktivitesi oto-enflamatuvar hastalık aktivite indeksi skoru kullanılarak değerlendirilmiş olup ≥9 puan aktif hastalık olarak kabul edildi. Serum IL-33 ve sST2 seviyeleri enzyme-linked immunosrobent assay kullanılarak çalışıldı. P-değeri <0,05 istatistiksel olarak anlamlı kabul edildi.

Bulgular: Serum IL-33 ve sST2 değerleri, FMF hastaları ve sağlıklı kontrol grubunda benzer bulundu [sırasıyla (p=0,899 ve p=0,614)]. Aktif (n=24) ve inaktif (n=52) FMF hastaları arasında da serum IL-33 ve sST2 değerleri arasında fark bulunamadı. Ancak, aktif FMF hastalarında serum C-reaktif protein ve serum amiloid A düzeylerinin inaktif hastalara göre istatistiksel olarak anlamlı bir şekilde daha yüksek olduğu görüldü (sırasıyla, p=0,001 ve p=0,002).

Sonuç: Bu çalışmada, her ne kadar IL-33, IL-1β ile benzer yapıya ve sinyalizasyon yolağına sahip olsa da FMF hastalarında serum düzeylerinin artmadığı ve hastalık aktivitesi ile de ilişkili olmadığı gösterilmiştir. Otoimmün hastalıklarla yapılan çalışmaların aksine, IL33/sST2 yolağının otoenflamatuvar hastalıklardaki rolünün ileri çalışmalarla incelenmesi gerekmektedir.

Anahtar Kelimeler

Ailevi Akdeniz Ateşi, İnterlökin-1β, İnterlökin-33, sST2

Etik Beyan

Destekleyen Kurum

Proje Numarası

Teşekkür

Kaynakça

1. Özen S, Batu ED, Demir S. Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management. Front Immunol. 2017;8:253.
2. Migita K, Asano T, Sato S, et al. Familial Mediterranean fever: overview of pathogenesis, clinical features and management. Immunol Med. 2018;41:55-61.
3. Alghamdi M. Familial Mediterranean fever, review of the literature. Clin Rheumatol. 2017;36:1707-1713.
4. Giancane G, Ter Haar NM, Wulffraat N, et al. Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis. 2015;74:635-641.
5. Chae JJ, Komarow HD, Cheng J, et al. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell. 2003;11:591-604.
6. Park H, Bourla AB, Kastner DL, et al. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol. 2012;12:570-580.
7. Onen F. Familial Mediterranean fever. Rheumatol Int. 2006;26:489-496.
8. Ozen S, Bilginer Y. A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol. 2014;10:135-147.
9. Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479-490.
10. Duan L, Chen J, Gong F, et al. The role of IL-33 in rheumatic diseases. Clin Dev Immunol. 2013;2013:924363.
11. Peine M, Marek RM, Löhning M. IL-33 in T Cell Differentiation, Function, and Immune Homeostasis. Trends Immunol. 2016;37:321-333.
12. Lloyd CM. IL-33 family members and asthma - bridging innate and adaptive immune responses. Curr Opin Immunol. 2010;22:800-806.
13. Hayakawa H, Hayakawa M, Kume A, et al. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem. 2007;282:26369-26380.
14. Matsuyama Y, Okazaki H, Tamemoto H, et al. Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritis. J Rheumatol. 2010;37:18-25.
15. Mok MY, Huang FP, Ip WK, et al. Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus. Rheumatology (Oxford). 2010;49:520-527.
16. Li XL, Lin TT, Qi CY, et al. Elevated serum level of IL-33 and sST2 in patients with ankylosing spondylitis: associated with disease activity and vascular endothelial growth factor. J Investig Med. 2013;61:848-851.
17. Yanaba K, Yoshizaki A, Asano Y, et al. Serum IL-33 levels are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. Clin Rheumatol. 2011;30:825-830.
18. Kim DJ, Baek SY, Park MK, et al. Serum level of interleukin-33 and soluble ST2 and their association with disease activity in patients with Behcet’s disease. J Korean Med Sci. 2013;28:1145-1153.
19. Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40:1879-1885.
20. Piram M, Koné-Paut I, Lachmann HJ, et al. Validation of the autoinflammatory diseases activity index (AIDAI) for hereditary recurrent fever syndromes. Ann Rheum Dis. 2014;73:2168-2173.
21. Cayrol C, Girard JP. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc Natl Acad Sci U S A. 2009;106:9021-9026.
22. Zhao Q, Chen G. Role of IL-33 and its receptor in T cell-mediated autoimmune diseases. Biomed Res Int. 2014;2014:587376.
23. Schnappauf O, Chae JJ, Kastner DL, et al. The Pyrin Inflammasome in Health and Disease. Front Immunol. 2019;10:1745.
24. Heilig R, Broz P. Function and mechanism of the pyrin inflammasome. Eur J Immunol. 2018;48:230-238.
25. Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16:407-420.
26. Miller AM. Role of IL-33 in inflammation and disease. J Inflamm (Lond). 2011;8:22.
27. Liew FY. IL-33: a Janus cytokine. Ann Rheum Dis. 2012;71 Suppl 2:i101-104.
28. Lüthi AU, Cullen SP, McNeela EA, et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity. 2009;31:84-98.
29. Duan L, Chen J, Gong F, et al. The role of IL-33 in rheumatic diseases. Clin Dev Immunol. 2013;2013:924363.
30. Rank MA, Kobayashi T, Kozaki H, et al. IL-33-activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol. 2009;123:1047- 1054.
31. Komai-Koma M, Xu D, Li Y, et al. IL-33 is a chemoattractant for human Th2 cells. Eur J Immunol. 2007;37:2779-2786.
32. Kurowska-Stolarska M, Kewin P, Murphy G, et al. IL-33 induces antigenspecific IL-5+ T cells and promotes allergic-induced airway inflammation independent of IL-4. J Immunol. 2008;181:4780-4790.
33. Oboki K, Nakae S, Matsumoto K, et al. IL-33 and Airway Inflammation. Allergy Asthma Immunol Res. 2011;3:81-88.
34. Aypar E, Ozen S, Okur H, et al. Th1 polarization in familial Mediterranean fever. J Rheumatol. 2003;30:2011-2013.
35. Simsek I, Pay S, Pekel A, et al. Serum proinflammatory cytokines directing T helper 1 polarization in patients with familial Mediterranean fever. Rheumatol Int. 2007;27:807-811.
36. Centola M, Wood G, Frucht DM, et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood. 2000;95:3223-3231.
37. Musabak U, Sengul A, Oktenli C, et al. Does immune activation continue during an attack-free period in familial Mediterranean fever? Clin Exp Immunol. 2004;138:526-533.
38. Sackesen C, Bakkaloglu A, Sekerel BE, et al. Decreased prevalence of atopy in paediatric patients with familial Mediterranean fever. Ann Rheum Dis. 2004;63:187-190.
39. Talabot-Ayer D, McKee T, Gindre P, et al. Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Joint Bone Spine. 2012;79:32-37.
40. Barbour M, Allan D, Xu H, et al. IL-33 attenuates the development of experimental autoimmune uveitis. Eur J Immunol. 2014;44:3320-3329.

Does IL33/Sst2 Pathway Play a Role in the Pathogenesis of Familial Mediterranean Fever?

Yıl 2022, Cilt: 75 Sayı: 3, 406 - 412, 18.10.2022

Ayşe Bahar Keleşoğlu Dinçer

Öz

Objectives: Interleukin-33 (IL-33) is a novel cytokine which belongs to IL-1 superfamily. It shares structural homology and common signaling pathway with IL-1β whose excessive secretion results in Familial Mediterranean Fever (FMF). In this study, we aimed to evaluate the serum IL-33 and its decoy receptor sST2 levels in patients with FMF and its correlation with disease activity.

Materials and Methods: In this cross-sectional single-centered study, 76 FMF patients and 30 age- and sex-matched healthy individuals were recruited. Disease activity was evaluated according to the autoinflammatory disease activity index, in which ≥9 points were considered as “active disease”. Serum IL-33 and sST2 levels were measured using a commercial enzyme-linked immunosorbent assay kit. A p-value <0.05 was considered statistically significant.

Results: Serum IL-33 and sST2 levels were similar in both groups (p=0.899 and p=0.614, respectively). Similarly, there were no statistically significant differences between active (n=24) and inactive (n=52) patients; however, serum C-reactive protein and amyloid-A levels were significantly higher in active FMF patients (p=0.001 and p=0.002, respectively).

Conclusion: This study has revealed that even though IL-33 is similar with IL-1β in terms of structure and signaling, it neither increased in sera of FMF patients nor correlated with disease activity. In contrast to previous studies conducted on autoimmune diseases, the role of IL33/sST2 pathway in autoinflammatory diseases needs to be further evaluated.

Anahtar Kelimeler

Familial Mediterranean Fever, Interleukin-1β, Interleukin-33, sST2

Etik Beyan

The study was approved by Ankara University Faculty of Medicine Ethics Board (approval number: 07-358-17).

Destekleyen Kurum

Proje Numarası

Teşekkür

Kaynakça

1. Özen S, Batu ED, Demir S. Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management. Front Immunol. 2017;8:253.
2. Migita K, Asano T, Sato S, et al. Familial Mediterranean fever: overview of pathogenesis, clinical features and management. Immunol Med. 2018;41:55-61.
3. Alghamdi M. Familial Mediterranean fever, review of the literature. Clin Rheumatol. 2017;36:1707-1713.
4. Giancane G, Ter Haar NM, Wulffraat N, et al. Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis. 2015;74:635-641.
5. Chae JJ, Komarow HD, Cheng J, et al. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell. 2003;11:591-604.
6. Park H, Bourla AB, Kastner DL, et al. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol. 2012;12:570-580.
7. Onen F. Familial Mediterranean fever. Rheumatol Int. 2006;26:489-496.
8. Ozen S, Bilginer Y. A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol. 2014;10:135-147.
9. Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479-490.
10. Duan L, Chen J, Gong F, et al. The role of IL-33 in rheumatic diseases. Clin Dev Immunol. 2013;2013:924363.
11. Peine M, Marek RM, Löhning M. IL-33 in T Cell Differentiation, Function, and Immune Homeostasis. Trends Immunol. 2016;37:321-333.
12. Lloyd CM. IL-33 family members and asthma - bridging innate and adaptive immune responses. Curr Opin Immunol. 2010;22:800-806.
13. Hayakawa H, Hayakawa M, Kume A, et al. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem. 2007;282:26369-26380.
14. Matsuyama Y, Okazaki H, Tamemoto H, et al. Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritis. J Rheumatol. 2010;37:18-25.
15. Mok MY, Huang FP, Ip WK, et al. Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus. Rheumatology (Oxford). 2010;49:520-527.
16. Li XL, Lin TT, Qi CY, et al. Elevated serum level of IL-33 and sST2 in patients with ankylosing spondylitis: associated with disease activity and vascular endothelial growth factor. J Investig Med. 2013;61:848-851.
17. Yanaba K, Yoshizaki A, Asano Y, et al. Serum IL-33 levels are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. Clin Rheumatol. 2011;30:825-830.
18. Kim DJ, Baek SY, Park MK, et al. Serum level of interleukin-33 and soluble ST2 and their association with disease activity in patients with Behcet’s disease. J Korean Med Sci. 2013;28:1145-1153.
19. Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40:1879-1885.
20. Piram M, Koné-Paut I, Lachmann HJ, et al. Validation of the autoinflammatory diseases activity index (AIDAI) for hereditary recurrent fever syndromes. Ann Rheum Dis. 2014;73:2168-2173.
21. Cayrol C, Girard JP. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc Natl Acad Sci U S A. 2009;106:9021-9026.
22. Zhao Q, Chen G. Role of IL-33 and its receptor in T cell-mediated autoimmune diseases. Biomed Res Int. 2014;2014:587376.
23. Schnappauf O, Chae JJ, Kastner DL, et al. The Pyrin Inflammasome in Health and Disease. Front Immunol. 2019;10:1745.
24. Heilig R, Broz P. Function and mechanism of the pyrin inflammasome. Eur J Immunol. 2018;48:230-238.
25. Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16:407-420.
26. Miller AM. Role of IL-33 in inflammation and disease. J Inflamm (Lond). 2011;8:22.
27. Liew FY. IL-33: a Janus cytokine. Ann Rheum Dis. 2012;71 Suppl 2:i101-104.
28. Lüthi AU, Cullen SP, McNeela EA, et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity. 2009;31:84-98.
29. Duan L, Chen J, Gong F, et al. The role of IL-33 in rheumatic diseases. Clin Dev Immunol. 2013;2013:924363.
30. Rank MA, Kobayashi T, Kozaki H, et al. IL-33-activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol. 2009;123:1047- 1054.
31. Komai-Koma M, Xu D, Li Y, et al. IL-33 is a chemoattractant for human Th2 cells. Eur J Immunol. 2007;37:2779-2786.
32. Kurowska-Stolarska M, Kewin P, Murphy G, et al. IL-33 induces antigenspecific IL-5+ T cells and promotes allergic-induced airway inflammation independent of IL-4. J Immunol. 2008;181:4780-4790.
33. Oboki K, Nakae S, Matsumoto K, et al. IL-33 and Airway Inflammation. Allergy Asthma Immunol Res. 2011;3:81-88.
34. Aypar E, Ozen S, Okur H, et al. Th1 polarization in familial Mediterranean fever. J Rheumatol. 2003;30:2011-2013.
35. Simsek I, Pay S, Pekel A, et al. Serum proinflammatory cytokines directing T helper 1 polarization in patients with familial Mediterranean fever. Rheumatol Int. 2007;27:807-811.
36. Centola M, Wood G, Frucht DM, et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood. 2000;95:3223-3231.
37. Musabak U, Sengul A, Oktenli C, et al. Does immune activation continue during an attack-free period in familial Mediterranean fever? Clin Exp Immunol. 2004;138:526-533.
38. Sackesen C, Bakkaloglu A, Sekerel BE, et al. Decreased prevalence of atopy in paediatric patients with familial Mediterranean fever. Ann Rheum Dis. 2004;63:187-190.
39. Talabot-Ayer D, McKee T, Gindre P, et al. Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Joint Bone Spine. 2012;79:32-37.
40. Barbour M, Allan D, Xu H, et al. IL-33 attenuates the development of experimental autoimmune uveitis. Eur J Immunol. 2014;44:3320-3329.

Toplam 40 adet kaynakça vardır.

Ayrıntılar

Birincil Dil	İngilizce
Konular	Romatoloji ve Artrit
Bölüm	Makaleler
Yazarlar	Ayşe Bahar Keleşoğlu Dinçer 0000-0001-8810-2869
Proje Numarası	-
Yayımlanma Tarihi	18 Ekim 2022
Yayımlandığı Sayı	Yıl 2022 Cilt: 75 Sayı: 3

Kaynak Göster

APA	Keleşoğlu Dinçer, A. B. (2022). Does IL33/Sst2 Pathway Play a Role in the Pathogenesis of Familial Mediterranean Fever?. Ankara Üniversitesi Tıp Fakültesi Mecmuası, 75(3), 406-412. https://doi.org/10.4274/atfm.galenos.2022.12599
AMA	Keleşoğlu Dinçer AB. Does IL33/Sst2 Pathway Play a Role in the Pathogenesis of Familial Mediterranean Fever?. Ankara Üniversitesi Tıp Fakültesi Mecmuası. Ekim 2022;75(3):406-412. doi:10.4274/atfm.galenos.2022.12599
Chicago	Keleşoğlu Dinçer, Ayşe Bahar. “Does IL33/Sst2 Pathway Play a Role in the Pathogenesis of Familial Mediterranean Fever?”. Ankara Üniversitesi Tıp Fakültesi Mecmuası 75, sy. 3 (Ekim 2022): 406-12. https://doi.org/10.4274/atfm.galenos.2022.12599.
EndNote	Keleşoğlu Dinçer AB (01 Ekim 2022) Does IL33/Sst2 Pathway Play a Role in the Pathogenesis of Familial Mediterranean Fever?. Ankara Üniversitesi Tıp Fakültesi Mecmuası 75 3 406–412.
IEEE	A. B. Keleşoğlu Dinçer, “Does IL33/Sst2 Pathway Play a Role in the Pathogenesis of Familial Mediterranean Fever?”, Ankara Üniversitesi Tıp Fakültesi Mecmuası, c. 75, sy. 3, ss. 406–412, 2022, doi: 10.4274/atfm.galenos.2022.12599.
ISNAD	Keleşoğlu Dinçer, Ayşe Bahar. “Does IL33/Sst2 Pathway Play a Role in the Pathogenesis of Familial Mediterranean Fever?”. Ankara Üniversitesi Tıp Fakültesi Mecmuası 75/3 (Ekim 2022), 406-412. https://doi.org/10.4274/atfm.galenos.2022.12599.
JAMA	Keleşoğlu Dinçer AB. Does IL33/Sst2 Pathway Play a Role in the Pathogenesis of Familial Mediterranean Fever?. Ankara Üniversitesi Tıp Fakültesi Mecmuası. 2022;75:406–412.
MLA	Keleşoğlu Dinçer, Ayşe Bahar. “Does IL33/Sst2 Pathway Play a Role in the Pathogenesis of Familial Mediterranean Fever?”. Ankara Üniversitesi Tıp Fakültesi Mecmuası, c. 75, sy. 3, 2022, ss. 406-12, doi:10.4274/atfm.galenos.2022.12599.
Vancouver	Keleşoğlu Dinçer AB. Does IL33/Sst2 Pathway Play a Role in the Pathogenesis of Familial Mediterranean Fever?. Ankara Üniversitesi Tıp Fakültesi Mecmuası. 2022;75(3):406-12.

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