Therapeutic potential of dinitrobenzene sulfonic acid (DNBS)-induced colitis in mice by targeting IL-1β and IL-18

Abstract

Interleukin (IL)-1 and IL-18 belong to the IL-1 family of ligands, and their receptors are members of the IL-1 receptor family. Both cytokines drive an extensive range of pro-inflammatory networks in many cell types using common signal transduction cascades. Anyway, differences in signaling pathways exist. With this aim in mind, we investigated by using transgenic mice the mechanisms through the simultaneous deficiency of both IL-1β and IL-18 could be more protective compared to blocking the single cytokine IL-1β or IL-18 during colitis.Colitis was provoked in mice by instillation of dinitrobenzene sulfonic acid (DNBS) in the colon. The results indicated that single knockout (KO) mice of IL-1β or IL-18, and double KO mice of both IL-1β and IL-18 were hyporesponsive to DNBS-induced colitis compared to wild type (WT) mice, in which double KO were less sensitive than single KO mice. Moreover, treatment with Anakinra (IL-1R antagonist) also ameliorated colitis, in views of macroscopic and histological alteration, infiltration of neutrophils or Th1 cells, oxidative and nitrosative stress. Anakinra more significantly reduced cyclooxygenase (COX-2) and nuclear factor (NF-κB) levels as well as IKB-α degradation compared to blocking IL-18. On the contrary, the absence of IL-18 reduced p-ERK and p-p38 mitogen-activated protein kinase (MAPKs) in a more significant way compared to blocking IL-1β. Thus, the double KO increased the protective effects against colon inflammation maybe because different converging inflammatory pathways are being inhibited.In conclusion, the blocking of both IL-1β and IL-18 function may be advantageous in the treatment of IBD or inflammatory diseases.