Primary Sjögren’s syndrome (pSS) represents a chronic, systemic autoimmune disorder, characterized by lymphocytic infiltration of exocrine glands, inducing compromised secretory function and tissue destruction. Increasing evidence had revealed that inflammatory mediators, such as nitric oxide (NO) and pro-inflammatory cytokines, are critical in the development and perpetuation of pSS systemic manifestations. In our current study, we aimed to investigate the ex vivo immunomodulatory effect of interferon (IFN)-β on iNOS expression, as well as on pro-inflammatory (tumor necrosis factor (TNF)-α, interleukin (IL)-6) and immunoregulatory (IL-10) cytokine production. Furthermore, we examined potential associations between the influence of IFN-β treatment on NO production, and pSS clinical and serological manifestations.
In 41 pSS patients documented for their clinical and serological features, NO and cytokines levels were measured by the Griess method and enzyme-linked immunosorbent assay, respectively. Inducible nitric oxide synthase expression was analyzed by fluorescence immunostaining assay, using peripheral blood mononuclear cells (PBMCs) isolated from healthy controls and pSS patients.
Our results revealed a strong down-modulating effect of IFN-β in the secretion of pro-inflammatory mediators including TNF-α, IL-6, and NO production. Interestingly, IFN-β exerts an increase in IL-10 levels. The most suppressive effect exerted by IFN-β on NO production was importantly reported for patients with neurological manifestation. This immunomodulatory effect of IFN-β on NO production is highly related to the decrease of inducible nitric oxide synthase (iNOS) expression.
Our findings highlight a consistent ex vivo inhibitory effect of IFN-β on pro-inflammatory cytokine production and NO pathway in pSS patients. Our data suggest that IFN-β could represent a potential candidate for targeting inflammation during pSS.
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Inducible NO synthase
Nuclear factor kappa B
Peripheral blood mononuclear cells
Primary Sjögren’s syndrome
Arroul-Lammali A, Rahal F, Chetouane R et al (2017) Ex vivo all-trans retinoic acid modulates NO production and regulates IL-6 effect during rheumatoid arthritis: a study in Algerian patients. Immunopharmacol Immunotoxicol 39:87–96
Belguendouz H, Messaoudene D, Lahmar K et al (2011) Interferon-γ and nitric oxide production during Behcet uveitis: immunomodulatory effect of interleukin-10. J Interferon Cytokine Res 31:643–651
Belkhelfa M, Rafa H, Medjeber O et al (2014) IFN-γ and TNF-α are involved during Alzheimer disease progression and correlate with nitric oxide production: a study in Algerian patients. J Interferon Cytokine Res 34:839–847
Benchabane S, Boudjelida A, Toumi R et al (2016) A case for IL-6, IL-17A, and nitric oxide in the pathophysiology of Sjogren’s syndrome. Int J Immunopathol Pharmacol 29:386–397
Benchabane S, Belguendouz H, Behairi N et al (2018) Cardamonin inhibits pro-inflammatory cytokine production and suppresses NO pathway in PBMCs from patients with primary Sjogren’s syndrome. Immunopharmacol Immunotoxicol 40(2):126–133
Boivin N, Baillargeon J, Doss PMIA et al (2015) Interferon-β suppresses murine Th1 cell function in the absence of antigen-presenting cells. PLoS ONE 10:e0124802
Colonna M, Trinchieri G, Liu YJ (2004) Plasmacytoid dendritic cells in immunity. Nat Immunol 5:1219–1226
De Luca G, Lugaresi A, Iarlori C et al (1998) Interferon beta normalizes suppressor cell function in dysimmune neuropathies. J Neuroimmunol 82:1–4
Dhib-Jalbut S, Marks S (2010) Interferon-beta mechanisms of action in multiple sclerosis. Neurology 74:S17–S24
El-behi M, Rostami A, Ciric B (2010) Current views on the roles of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. J Neuroimmune Pharmacol 5:189–197
Ferro F, Marcucci E, Orlandi M et al (2017) One year in review primary Sjögren’s syndrome. Clin Exp Rheumatol 35(2):179–191
Griffith OW, Stuehr DJ (1995) NO synthases: properties and catalytic mechanism. Annu Rev Physiol 57:707–736
Inogés S, Merino J, Bandrés E et al (1999) Cytokine flow cytometry differentiates the clinical status of multiple sclerosis patients. Clin Exp Immunol 115:521–525
Ioannidis JP, Vassiliou VA, Moutsopoulos HM (2002) Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren’s syndrome. Arthritis Rheum 46:741–747
Iyer SS, Cheng G (2012) Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol 32(1):23–63
Kasper LH, Reder AT (2014) Immunomodulatory activity of interferon-beta. Ann Clin Transl Neurol 1:622–631
Konttinen YT, Platts LA, Tuominen S et al (1997) Role of NO in Sjogren’s syndrome. Arthritis Rheum 40:875–883
Korn T, Mitsdoerffer M, Croxford AL et al (2008) IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc Natl Acad Sci 105:18460–18465
Le Bon A, Schiavoni G, D’Agostino G et al (2001) Type I interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 14:461–470
Mavragani CP, Moutsopoulos HM (2010) The geoepidemiology of Sjögren’s syndrome. Autoimmun Rev 9:305–310
Moutsopoulos HM (2004) Sjogren’s syndrome: a forty-year scientific journey. J Autoimmun 51:1–9
Noronha A, Toscas A, Jensen MA (1993) Interferon beta decreases T cell activation and interferon gamma production in multiple sclerosis. J Neuroimmunol 46:145–153
Rafa H, Amri M, Saoula H et al (2010) Involvement of interferon-γ in bowel disease pathogenesis by nitric oxide pathway: a study in Algerian patients. J Interferon Cytokine Res 30:691–697
Rangachari M, Zhu C, Sakuishi K et al (2012) Bat3 promotes T cell responses and autoimmunity by repressing Tim-3—mediated cell death and exhaustion. Nat Med 18:1394–1400
Reder AT, Velichko S, Yamaguchi KD et al (2008) IFN-β1b induces transient and variable gene expression in relapsing-remitting multiple sclerosis patients independent of neutralizing antibodies or changes in IFN receptor RNA expression. J Interferon Cytokine Res 28:317–331
Routsias JG, Goules JD, Charalampakis G et al (2013) Malignant lymphoma in primary Sjögren’s syndrome: an update on the pathogenesis and treatment. Semin Arthritis Rheum 43:178–186
Skopouli FN, Dafni U, Ioannidis JP et al (2000) Clinical evolution, and morbidity and mortality of primary Sjögren’s syndrome. Semin Arthritis Rheum 29:296–304
Tarpley TM Jr, Anderson LG, White CL (1974) Minor salivary gland involvement in Sjogren’s syndrome. Oral Surg Oral Med Oral Pathol 37:64–74
Theofilopoulos AN, Baccala R, Beutler B et al (2005) Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 23:307–336
Torkildsen Ø, Myhr K-M, Bø L (2016) Disease-modifying treatments for multiple sclerosis– a review of approved medications. Eur J Neurol 23:18–27
Touil-Boukoffa C, Bauvois B, Sanceau J et al (1998) Production of nitric oxide (NO) in human hydatidosis: relationship between nitrite production and interferon gamma levels. Biochimie 80:739–744
Ugar-ankal D, Ozmeric N (2006) A multifaceted molecule, nitric oxide in oral and periodontal diseases. Clin Chim Acta 366:90–100
Vitali C, Bombardieri S, Jonsson R et al (2002) Classification criteria for Sjogren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554–558
Voulgarelis M, Ziakas PD, Papageorgiou A et al (2012) Prognosis and outcome of non-Hodgkin lymphoma in primary Sjögren’s syndrome. Medicine 91:1–9
Wanchu A, Khullar M, Sud A et al (2000) Elevated nitric oxide production in patients with primary Sjogren’s syndrome. Clin Rheumatol 19:360–364
Wang Q, Mao-Draayer Y (2015) Interferon beta treatment exerts potential neuroprotective effects through neurotrophic factors and novel neurotensin/neurotensin high affinity receptor 1 pathway. Neural Regener Res 10(12):1932–1933
Youinou P, Pers JO (2015) Primary Sjögren’s syndrome at a glance today. Joint Bone Spine 82:75–76
Youinou P, Saraux A, Pers JO (2012) B lymphocytes govern the pathogenesis of Sjögren’s syndrome. Curr Pharm Biotechnol 3:2071–2077
Zhu C, Anderson AC, Schubart A et al (2005) The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6:1245–1252
Zidi S, Bediar-Boulaneb F, Belguendouz H et al (2017) Local pro-inflammatory cytokine and nitric oxide responses are elevated in patients with pterygium. Int J Immunopathol Pharmacol 30(4):395–405
This work was supported by national thematic research agency in development health science (ATRSS, ex ANDRS), Project Code N°43-ANDRS-2011.
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Benchabane, S., Belkhelfa, M., Belguendouz, H. et al. Interferon-β inhibits inflammatory responses mediators via suppression of iNOS signaling pathway in PBMCs from patients with primary Sjögren’s syndrome. Inflammopharmacol 26, 1165–1174 (2018). https://doi.org/10.1007/s10787-018-0499-4
- Primary Sjögren’s syndrome
- Nitric oxide