Skip to main content
SpringerLink
Log in

RAC1 expression and role in IL-1β production and oxidative stress generation in familial Mediterranean fever (FMF) patients

  • Original Article
  • Published:
European Cytokine Network Aims and scope

Abstract

Objectives

Familial Mediterranean fever (FMF) is a recessively inherited autoinflammatory disorder. The caspase-1-dependent cytokine, IL-1β, plays an important role in FMF pathogenesis, and RAC1 protein has been recently involved in IL-1β secretion. This study aims to investigate RAC1 expression and role in IL-1β and caspase-1 production and oxidative stress generation in FMF.

Materials and methods

The study included 25 FMF patients (nine during attack and remission, and 16 during remission only), and 25 controls. RAC1 expression levels were analyzed by real-time PCR. Ex vivo production of caspase-1, IL-1β, IL-6 and markers of oxidative stress (malondialdehyde, catalase, and glutathione system) were evaluated respectively in supernatants of patients’ and controls’ PBMC and PMN cultures, in the presence and absence of RAC1 inhibitor.

Results

RAC1 gene expression and IL-1β levels were increased in patients in crises compared to those in remission or controls. RAC1 expression levels were correlated with MEFV genotypes, patients carrying the M694V/M694V genotype having a two-fold increase in the expression levels compared to those carrying other genotypes. Caspase-1 levels were higher in LPS-induced PBMC of patients in remission than controls. Spontaneous and LPS-induced IL-1β production were comparable in patients in remission and controls, whereas LPS-induced IL-6 production was enhanced in patients, compared to controls. RAC1 inhibition resulted in a decrease in caspase-1 and IL-1β, but not IL-6, levels. Malondialdehyde levels produced by LPS-stimulated PMNs were increased in patients in remission compared to those in controls, but decreased following RAC1 inhibition. Catalase and GSH activities were reduced in unstimulated PMN culture supernatants of patients in remission compared to controls and were increased in the presence of RAC1 inhibitor.

Conclusion

These results show the involvement of RAC1 in the inflammatory process of FMF by enhancing IL-1β production, through caspase-1 activation, and generating oxidative stress, even during asymptomatic periods.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sohar E, Gafni J, Pras M, Heller H. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 1967; 43: 227–53.

    Article  CAS  PubMed  Google Scholar 

  2. Medlej-Hashim M, Loiselet J, Lefranc G, Mégarbané A. Familial Mediterranean fever (FMF): from diagnosis to treatment. Santé 2004; 14: 261–6.

    PubMed  Google Scholar 

  3. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997; 17: 25–31.

    Article  Google Scholar 

  4. International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 1997; 90: 797–807.

    Article  Google Scholar 

  5. 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: 3223–31.

    CAS  PubMed  Google Scholar 

  6. Papin S, Cuenin S, Agostini L, et al. The SPRY domain of pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β processing. Cell Death Differ 2007; 14: 1457–66.

    Article  CAS  PubMed  Google Scholar 

  7. Chae JJ, Wood G, Masters SL, et al. The B30. 2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1β production. Proc Natl Acad Sci U S A 2006; 103: 9982–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yu JW, Wu J, Zhang Z, et al. Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization. Cell Death Differ 2005; 13: 236–49.

    Article  CAS  Google Scholar 

  9. Shamaa OR, Mitra S, Gavrilin MA, Wewers MD. Monocyte caspase-1 is released in a stable, active high molecular weight complex distinct from the unstable cell lysate-activated caspase-1. PLoS One 2015; 10: e0142203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lopez-Castejon G, Brough D. Understanding the mechanism of IL-1β secretion. Cytokine Growth Factor Rev 2011; 22: 189–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 2011; 117: 3720–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ibrahim J-N, Isabelle J, Lecron J-C, Medlej-Hashim M. Cytokine signatures in hereditary fever syndromes (HFS). Cytokine Growth Factor Rev 2016; S1359-6101:30103–4 (PubMed — NCBI).

    Google Scholar 

  13. Ibrahim J-N, Jounblat R, Delwail A, et al. Ex vivo PBMC cytokine profile in familial Mediterranean fever patients: involvement of IL-1β, IL-1α and Th17-associated cytokines and decrease of Th1 and Th2 cytokines. Cytokine 2014; 69: 248–54.

    Article  CAS  PubMed  Google Scholar 

  14. Normand S, Massonnet B, Delwail A, et al. Specific increase in caspase-1 activity and secretion of IL-1 family cytokines: a putative link between mevalonate kinase deficiency and inflammation. Eur Cytokine Netw 2009; 20: 101–7.

    CAS  PubMed  Google Scholar 

  15. Kuijk LM, Beekman JM, Koster J, Waterham HR, Frenkel J, Coffer PJ. HMG-CoA reductase inhibition induces IL-1 release through Rac1/PI3K/PKB-dependent caspase-1 activation. Blood 2008; 112: 3563–73.

    Article  CAS  PubMed  Google Scholar 

  16. Eitel J, Meixenberger K, van Laak C, et al. Rac1 regulates the NLRP3 inflammasome which mediates IL-1beta production in Chlamydophila pneumoniae infected human mononuclear cells. PLoS One 2012; 7: e30379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Heller H, Sohar E, Sherf L. Familial Mediterranean fever. AMA Arch Intern Med 1958; 102: 50–71.

    Article  CAS  PubMed  Google Scholar 

  18. Gastonguay A, Berg T, Hauser AD, Schuld N, Lorimer E, Williams CL. The role of Rac1 in the regulation of NF-kB activity, cell proliferation, and cell migration in non-small cell lung carcinoma. Cancer Biol Ther 2012; 13: 647–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sanlioglu S, Williams CM, Samavati L, et al. Lipopolysaccharide induces Rac1-dependent reactive oxygen species formation and coordinates tumor necrosis factor-alpha secretion through IKK regulation of NF-kappa B. J Biol Chem 2001; 276: 30188–98.

    Article  CAS  PubMed  Google Scholar 

  20. Raz L, Zhang Q-G, Zhou C, et al. Role of Rac1 GTPase in NADPH oxidase activation and cognitive impairment following cerebral ischemia in the rat. PLoS One 2010; 5: e12606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Patil S. Important role for Rac1 in regulating reactive oxygen species generation and pulmonary arterial smooth muscle cell growth. Am J Physiol Lung Cell Mol Physiol 2004; 287: L1314–22.

    Article  CAS  PubMed  Google Scholar 

  22. Dalbeth N, Lauterio TJ, Wolfe HR. Mechanism of action of colchicine in the treatment of gout. Clin Ther 2014; 36: 1465–79.

    Article  CAS  PubMed  Google Scholar 

  23. Barth BM, Stewart-Smeets S, Kuhn TB. Proinflammatory cytokines provoke oxidative damage to actin in neuronal cells mediated by Rac1 and NADPH oxidase. Mol Cell Neurosci 2009; 41: 274–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Muise AM, Walters T, Xu W, et al. Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis. Gastroenterology 2011; 141: 633–41.

    Article  CAS  PubMed  Google Scholar 

  25. Bourgine J, Garat A, Allorge D, et al. Evidence for a functional genetic polymorphism of the Rho-GTPase Rac1. Implication in azathioprine response? Pharmacogenet Genomics 2011; 21: 313–24.

    Article  CAS  PubMed  Google Scholar 

  26. Ibrahim J-N, Chouery E, Lecron J-C, Mégarbané A, Medlej-Hashim M. Study of the association of IL-1β and IL-1RA gene polymorphisms with occurrence and severity of Familial Mediterranean fever. Eur J Med Genet 2015; 58: 668–73.

    Article  PubMed  Google Scholar 

  27. Ediz L, Ozkol H, Tekeoglu I, Tuluce Y, Gulcu E, Koyuncu I. Increased oxidative stress in patients with familial Mediterranean fever during attack period. Afr Health Sci 2011; 11: 6–13.

    Article  Google Scholar 

  28. Guzel S, Andican G, Seven A, et al. Acute phase response and oxidative stress status in familial Mediterranean fever (FMF). Mod Rheumatol 2011; 22: 431–7.

    Article  PubMed  Google Scholar 

  29. Michel F, Bonnefont-Rousselot D, Mas E, Drai J, Thérond P. Biomarqueurs de la peroxydation lipidique: aspects analytiques. Ann Biol Clin (Paris) 2008: 605–20.

  30. Deshpande SS. Constitutive activation of rac1 results in mitochondrial oxidative stress and induces premature endothelial cell senescence. Arterioscler Thromb Vasc Biol 2002; 23: 1e–6.

    Google Scholar 

  31. Khanday FA, Yamamori T, Mattagajasingh I, et al. Rac1 leads to phosphorylation-dependent increase in stability of the p66shc adaptor protein: role in Rac1-induced oxidative stress. Mol Biol Cell 2006; 17: 122–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ozen S, Uckan D, Baskin E, et al. Increased neutrophil apoptosis during attacks of familial Mediterranean fever. Clin Exp Rheumatol 2001; 19: S68–71.

    CAS  PubMed  Google Scholar 

  33. Spolarics Z, Wu J-X. Role of glutathione and catalase in H2O2 detoxification in LPS-activated hepatic endothelial and Kupffer cells. Am J Physiol 1997; 273: G1304–11.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Life and Earth Sciences, Faculty of Sciences II, Lebanese University, Box 90656, Jdeidet El Metn, Fanar, Lebanon

    José-Noel Ibrahim, Rania Jounblat, Cynthia Al Hageh & Myrna Medlej-Hashim

  2. Laboratoire inflammation, tissus épithéliaux et cytokines (LITEC), CHU of Poitiers, University of Poitiers, EA4331, Poitiers, France

    José-Noel Ibrahim & Jean-Claude Lecron

  3. Faculty of Medicine, Medical Genetics Unit, Saint Joseph University, Beirut, Lebanon

    Nadine Jalkh, Joelle Abou Ghoch & Eliane Chouery

  4. Institut Jérôme Lejeune, Paris, France

    André Mégarbané

Authors
  1. José-Noel Ibrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rania Jounblat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nadine Jalkh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joelle Abou Ghoch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cynthia Al Hageh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eliane Chouery
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. André Mégarbané
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean-Claude Lecron
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Myrna Medlej-Hashim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Myrna Medlej-Hashim.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ibrahim, JN., Jounblat, R., Jalkh, N. et al. RAC1 expression and role in IL-1β production and oxidative stress generation in familial Mediterranean fever (FMF) patients. Eur Cytokine Netw 29, 127–135 (2018). https://doi.org/10.1684/ecn.2018.0416

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1684/ecn.2018.0416

Keywords

Search

Navigation