Epithelial overexpression of interleukin-32α in inflammatory bowel disease

Abstract

SummaryInterleukin (IL)-32 is a recently described proinflammatory cytokine, characterized by induction of nuclear factor (NF)-kB activation. We studied IL-32a expression in the inflamed mucosa of inflammatory bowel disease (IBD). We also investigated mechanisms regulating IL-32a expression. Tissue samples were obtained endoscopically or surgically from patients with ulcerative colitis (UC) (n = 10), Crohn's disease (CD) (n = 10), ischaemic colitis (n = 4) and normal colorectal tissues (n = 10). IL-32a expression was evaluated by standard immunohistochemical procedure. IL-32 mRNA expression was analysed by Northern blot. IL-32a was expressed weakly by colonic epithelial cells from normal individuals and subjects with ischaemic colitis. In the inflamed mucosa of IBD patients, epithelial IL-32a expression was increased markedly. In UC and CD patients, IL-32a expression was enhanced in affected mucosa compared to non-affected mucosa. In intestinal epithelial cell lines, expression of IL-32a mRNA and protein was enhanced by IL-1b, interferon (IFN)-g and tumour necrosis factor (TNF)-a. A combination of TNF-a plus IFN-g exerted synergistic effects. IL-32a induction by IL-1b and/or TNF-a was mediated by NF-kB activation. Epithelial IL-32a expression was increased in IBD patients, and in CD patients in particular. IL-32a might be involved in the pathophysiology of IBD as a proinflammatory cytokine and a mediator of innate immune response.

Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

“…Because CD is often treated with neutralizing anti-TNFα antibodies and because of the role of endogenous IL-32 in the induction of TNFα, we expected that IL-32γ TG mice would exhibit an exaggerated course of colitis when subjected to DSS. We postulated that the responses to DSS in the inflamed intestinal epithelium would be amplified by IL-32γ-induced TNFα secretion from monocytes stimulated by IL-32γ from the intestinal epithelial cells (17). Indeed, the severity of the model during the early phase of DSS colitis was modestly exacerbated.…”

“…In the present study, we sought to characterize a role for IL-32 in IBD because IL-32 has been implicated in CD (11) as well as in UC (17). Because CD is often treated with neutralizing anti-TNFα antibodies and because of the role of endogenous IL-32 in the induction of TNFα, we expected that IL-32γ TG mice would exhibit an exaggerated course of colitis when subjected to DSS.…”

“…On the other hand, silencing of endogenous IL-32 by either siRNA or shRNA results in decreased IL-1β, IL-8, and TNFα production (8,12,15) or IL-6 induced by IL-1β (16). Furthermore, IL-32 is present in the intestinal tissue of patients with CD (11) or UC (17).…”

Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function

“…Microarray gene expression analysis of HS5 and HS27a cells revealed prominent induction of IL-32 by TNF␣ (12). Because IL-32 appears to contribute to inflammatory and autoimmune diseases (13)(14)(15)(16) and induces TNF␣ and apoptosis (17), we hypothesized that IL-32 and TNF␣ participate in an autoamplification loop in MDS that promotes apoptosis. Therefore, the levels of TNF␣, IL-32, or both should be lower in patients in whom proliferation, rather than apoptosis, was the dominant feature.…”

Intracellular Interaction of Interleukin (IL)-32α with Protein Kinase Cϵ (PKCϵ) and STAT3 Protein Augments IL-6 Production in THP-1 Promonocytic Cells

“…Elevated IL-32 levels have been associated with several inflammatory diseases, such as chronic obstructive pulmonary disease (1), rheumatoid arthritis (2), and Crohn disease (3).…”