The Melanocortin System in Inflammatory Bowel Diseases: Insights into Its Mechanisms and Therapeutic Potentials

Abstract

The melanocortin system is a complex set of molecular mediators and receptors involved in many physiological and homeostatic processes. These include the regulation of melanogenesis, steroidogenesis, neuromodulation and the modulation of inflammatory processes. In the latter context, the system has assumed importance in conditions of chronic digestive inflammation, such as inflammatory bowel diseases (IBD), in which numerous experiences have been accumulated in mouse models of colitis. Indeed, information on how such a system can counteract colitis inflammation and intervene in the complex cytokine imbalance in the intestinal microenvironment affected by chronic inflammatory damage has emerged. This review summarises the evidence acquired so far and highlights that molecules interfering with the melanocortin system could represent new drugs for treating IBD.

Keywords: ACTH; Crohn’s disease; KPV; KdPT; inflammatory bowel disease; melanocortin; melanocortin receptors; ulcerative colitis; α-MSH; β-MSH.

Figure 1

The strategy of α-melanocyte-stimulating hormone (α-MSH) release at the intestinal level in experimental colitis by recombinant bacteria. Two main bacterial strains (i.e., Lactobacillus casei and Bifidobacterium longum) were recombined using two different plasmids (i.e., pLUAT-ss-MSH or pBDMSH) and made α-MSH producers. This strategy was effective in models of dextran sulphate sodium-induced experimental colitis in mice. The anti-inflammatory efficacy was mainly weighed against a reduction in myeloperoxidase (MPO) activity (a harbinger of neutrophilic tissue infiltration and thus reflective of intratissue inflammatory activity) and a modulation of the imbalance between pro- and anti-inflammatory cytokines, as tumour necrosis factor (TNF), interleukins (IL) or nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκB-α).

Figure 2

Structure of the tripeptides KPV (A), Lys-Pro-Val, and KdPT (B), Lys-D-Pro-Thr. The two peptides have been defined several times in the literature as structurally similar. KdPT is homologous to the 193–195 amino acids of interleukin 1β.