IL-23/IL-17A Axis Correlates with the Nitric Oxide Pathway in Inflammatory Bowel Disease: Immunomodulatory Effect of Retinoic Acid

Abstract

Inflammatory bowel diseases (IBDs) are chronic inflammatory diseases of the gastrointestinal tract, which are clinically present as 1 of the 2 disorders, Crohn's disease (CD) or ulcerative colitis (UC) (Rogler 2004). The immune dysregulation in the intestine plays a critical role in the pathogenesis of IBD, involving a wide range of molecules, including cytokines. The aim of this work was to study the involvement of T-helper 17 (Th17) subset in the bowel disease pathogenesis by the nitric oxide (NO) pathway in Algerian patients with IBD. We investigated the correlation between the proinflammatory cytokines [(interleukin (IL)-17, IL-23, and IL-6] and NO production in 2 groups of patients. We analyzed the expression of messenger RNAs (mRNAs) encoding Th17 cytokines, cytokine receptors, and NO synthase 2 (NOS2) in plasma of the patients. In the same way, the expression of p-signal transducer and activator of transcription 3 (STAT3) and NOS2 was measured by immunofluorescence and immunohistochemistry. We also studied NO modulation by proinflammatory cytokines (IL-17A, IL-6, tumor necrosis factor α, or IL-1β) in the presence or absence of all-trans retinoic acid (At RA) in peripheral blood mononuclear cells (PBMCs), monocytes, and in colonic mucosa cultures. Analysis of cytokines, cytokine receptors, and NOS2 transcripts revealed that the levels of mRNA transcripts of the indicated genes are elevated in all IBD groups. Our study shows a significant positive correlation between the NO and IL-17A, IL-23, and IL-6 levels in plasma of the patients with IBD. Interestingly, the correlation is significantly higher in patients with active CD. Our study shows that both p-STAT3 and inducible NOS expression was upregulated in PBMCs and colonic mucosa, especially in patients with active CD. At RA downregulates NO production in the presence of proinflammatory cytokines for the 2 groups of patients. Collectively, our study indicates that the IL-23/IL-17A axis plays a pivotal role in IBD pathogenesis through the NO pathway.

Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases

“…In fact, increased levels of NO were found in the serum, stool, and urine of patients in the active phase of UC and CD compared to those in the inactive phase [26,29] . Our study [16,17] showed significantly higher serum levels of NO in CD patients compared to UC patients. However, data from previous studies reported no significant differences between these two categories of disease, whereas higher systemic levels of NO in UC compared to CD was found [16,17,26,29] .…”

“…Our study [16,17] showed significantly higher serum levels of NO in CD patients compared to UC patients. However, data from previous studies reported no significant differences between these two categories of disease, whereas higher systemic levels of NO in UC compared to CD was found [16,17,26,29] . A significant difference was observed in the NO concentrations between the active and inactive phase of the disease.…”

“…A significant difference was observed in the NO concentrations between the active and inactive phase of the disease. This observation suggests a possible use of serum NO levels for monitoring disease activity in both types of IBD [16,28,29] . While several studies conducted using animal models indicate the deleterious effect of NO, recent studies have shown that NO may also exert a protective effect against colitis [29][30][31][32] .…”

“…Interestingly, Both Th1 and Th17 cytokines are involved in the up-regulation of iNOS expression in IBD. Indeed, a positive correlation between NO production and increased pro-inflammatory cytokine levels (e.g., TNF-α, IL-6, IL-17 IL-12 and IFN-γ) have been reported in IBD plasma [16,17] . Considerable research has been conducted over the past year to better understand the pathogenesis of IBD, and has led to the development of novel therapeutic strategies based on targeting cytokines, their receptors, as well as the modulation of NO.…”

“…In contrast, UC is viewed similar to an atypical Th2 type immune response which generates high levels of IL-5, IL-4, and IL-13 [13,14] . In addition, several studies have shown the involvement of Th17 type cytokines (i.e., IL-17, IL-23, IL-22, and IL-6) in the pathogenic process of both CD and UC [15,16] . Interestingly, Both Th1 and Th17 cytokines are involved in the up-regulation of iNOS expression in IBD.…”