Interleukin 12/interleukin 23 pathway: Biological basis and therapeutic effect in patients with Crohn's disease

Abstract

Considering that both innate and adaptive immune responses are involved in the pathogenesis of Crohn’s disease (CD), novel therapeutic options have significantly been developed. Biological agents represent an important addition to the conventional treatments for immuno-inflammatory conditions, acting as antagonists of adhesion molecules or various inflammatory cytokines. The interleukin 12 (IL-12)/IL-23 common pathway has been found to play a determinant role in the induction of inflammation in adaptive immune responses. In particular, IL-23 promotes the differentiation of naïve T helper cells into Th17 phenotype with the concomitant secretion of several inflammatory cytokines such as IL-17 and IL-22, whereas IL-12 induces the Th1 polarization and production of critical cytokines such as interferon-γ and tumor necrosis factor. Nowadays, there is increased interest regarding the role of IL-23 as a therapeutic target of CD through the blockage of IL-23 mediated pathways. In this editorial, we focus on the role of IL-12/IL-23 pathway in the regulation of mucosal immunity and in the induction and maintenance of chronic inflammation. In parallel, we critically discuss the available data regarding the therapeutic effect of the IL-12/IL-23 inhibitors and especially of ustekinumab, a human monoclonal antibody which has been recently approved by the United States Food and Drug Administration for the management of moderate-to-severe CD and its potential to be used as first-line therapy in everyday clinical practice.

Keywords: Crohn’s disease, Interleukin 12, Interleukin 23, Monoclonal antibodies, Ustekinumab, Biological agents, Interleukin 12/interleukin 23 blockade

Core tip: The therapeutic management of Crohn’s disease patients not responding to treatment with anti-tumor necrosis factor agents remains a clinical challenge. Recently, there has been increased evidence regarding the development of new drugs with alternative mechanisms of action. Interleukin (IL)-12 and IL-23 are important cytokines which are involved in the adaptive immune responses and their common pathway has been found to play a determinant role in the induction of inflammation. Clinical trials have assessed the therapeutic effect of an IL-12/IL-23 inhibitor (ustekinumab), demonstrating rapid clinical effect with a safety profile. Further studies are needed to elucidate its potential role as first-line therapy in Crohn’s disease.