Ex vivoimmunomodulatory effect of all-trans-retinoic acid during Behçet’s disease: a study in Algerian patients

Abstract

Uveitis, recurrent oral and genital ulcerations associated with skin lesions are the major symptoms of a chronic multisystemic inflammatory disorder known as Behçet's disease (BD). High prevalence of this dreaded disease has been observed in the Mediterranean basin, including Algeria and along the Silk Road. Although the etiologic agent of this disease remains uncertain, many hypotheses have been advanced in its pathogenesis. Our team has previously reported high levels of nitric oxide (NO) in sera of BD patients, suggesting its deleterious effect during chronic inflammation. In our current study, the aim is to investigate the ex vivo immunomodulatory effect of all-trans-retinoic acid (ATRA) on NO pathway in Algerian BD patients. First, peripheral blood mononuclear cells isolated from active and inactive BD patients and healthy controls were cultured with different concentrations of ATRA. NO production was estimated with the Griess method. To elucidate the underlying mechanisms of ATRA effect on NO production, we analyze inducible nitric oxide synthase expression and nuclear factor-κB (NF-κB) activity by immunofluorescence test. Our results revealed a higher production of NO in active BD compared with the inactive stage and healthy controls. We observed that ATRA inhibits NO production in BD both in active and inactive stages and inhibits NF-κB translocation. In conclusion, we report a relationship between NO production and the disease activity. ATRA down-regulates NO production in BD patients. This immunomodulatory effect seems to be mediated through NF-κB pathway. All these findings suggest that ATRA could be considered as a promising therapy for BD.

All-<b><i>trans</i></b>-Retinoic Acid Modulates Nitric Oxide and Interleukin-17A Production by Peripheral Blood Mononuclear Cells from Patients with Alzheimer's Disease

“…In our present study, ATRA significantly downmodulated in vitro NO production in AD patients. Our data are consistent with the findings reported by Rafa et al [48] and Djeraba et al [49] in inflammatory bowel diseases and Behçet disease, respectively. Similar results have been shown by many studies conducted on rat microglia [50,51].…”

“…Similar results have been shown by many studies conducted on rat microglia [50,51]. Consistent with several findings from other groups [49,52,53], our results suggest that ATRA can inhibit NO production in AD cells by regulating iNOS expression. Other research groups have reported a relationship between anti-inflammatory effects of retinoids and inhibition of the NF-κB and JAK/STAT signaling pathways [49,54,55].…”

“…Furthermore, higher systemic levels of β-carotene have been associated with better cognitive performance in older persons [46,47]. In addition to their antioxidant properties, RAs can suppress inflammation and modulate immune responses in numerous inflammatory and autoimmune diseases [48,49]. In AD, it has been reported that RAs can affect several mechanisms related to the disease [32].…”

Effects of All-<i>Trans</i> Retinoic Acid on Lipopolysaccharide-Induced Synovial Explant

“…Neither conventional treatments nor biologic diseasemodifying therapies can exert definite curative effects on RA. All-trans retinoic acid (ATRA) has received widespread attention as an active vitamin A derivative and an immune inflammation inhibitor (7), in addition to its ability to cure acute promyelocytic leukemia (APL) (8) and acne (9). With regard to the role of ATRA in immune inflammatory responses, ATRA reportedly participates in ameliorating inflammatory response in the epididymis by downregulating pro-inflammatory cytokines and upregulating anti-inflammatory factors (10).…”

In vivo and in vitro IL-18 production during uveitis associated with Behçet disease: Effect of glucocorticoid therapy

“…In a recent study, our team showed the over-expression of NF-B in Behçet patients PBMCs. Increased NF-B expression is concomitant with the overexpression of iNOS, the enzyme that produce NO [39]. In the same way, Hamzaoui et al reported increased IL-18 expression when they stimulated patients cells cultures (from broncho-alveolar lavage fluid) with LPS [25].…”