Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine and intracellular signalling molecule that is implicated in the pathogenesis of inflammatory bowel disease. Intestinal MIF concentrations are elevated in patients with IBD, and inhibition of MIF ameliorates disease activity in animal models. MIF has diverse effects. It is a pivotal mediator of innate immunity and released by immune and non-immune cells in response to both endogenous and exogenous factors. In turn, MIF stimulates the release of pro-inflammatory cytokines and mediates immune cell migration and activation through both direct and indirect mechanisms. In addition to traditional pro-inflammatory cytokine activities, MIF counter regulates the immunosuppressive effects of glucocorticoids through both local and pituitary release, and is a potent anti-apoptotic factor able to prolong the survival of tissue, inflammatory and tumour cells. In the GI tract MIF is constitutively expressed within the apical compartment of the epithelium and is predominantly secreted in an apical direction. Provisional evidence implicates MIF in several key patho-biological processes in IBD, in particular microbial sensing through both a moderating effect on M-cell function and as an effector molecule of TLR signalling; dendritic cell function; and also in the control of intestinal hypoxia and redox sensitivity and signalling.
Several small molecule inhibitors of MIF have been identified although none have reached clinical trials. MIF has recently been identified as the main cellular target of isothiocyanates, a group of plant-based chemicals that are present in cruciferous vegetables that are found in the human diet. In a proof of concept investigation, consumption of a large meal of watercress (a potent source of phenethyl isothiocyanate) was found to reduce human plasma MIF concentrations.
The anti-inflammatory effects of isothiocyanates as a novel therapy in IBD was investigated in a murine model of colitis. The dextran sulphate sodium (DSS) model of colitis was established, and a novel method of clinical disease scoring was developed and prospectively validated. Animals were dosed with isothiocyanates and the MIF inhibitory capacity was investigated. Animals were examined for evidence of toxicity and the efficacy of ITC in preventing DSS colitis was investigated. No significant beneficial treatment effect was observed. Indeed, significant gastric toxicity occurred following oral administration. Gastric toxicity from ITC has not been reported previously and the mode of action of this effect is unknown. In further experiments, the efficacy of rectally administered ITC was investigated. Although a pilot investigation showed a marked effect, in subsequent experiments, no statistically significant effect was observed. No toxicicity was observed in the colon following rectal administration.
The contribution of two functional promoter polymorphisms of MIF to IBD susceptibility and phenotype was investigated. The investigation, the largest of its kind, aimed to define the contribution of MIF variants to IBD risk in the Canterbury population, and to resolve, through meta-analysis, discordance in results from previous investigations. Within the Canterbury data set, no evidence was found for an association between either variant, whether considered individually or together, with respect to IBD risk, phenotype, disease behaviour or clinical course. A weak trend toward protection against ileal CD and MIF-173C was observed. With respect to rs755622; meta-analysis found no significant association between MIF-173C and risk of UC, CD or overall IBD. These data do not undermine the importance of MIF to the pathobiology of IBD, but emphasise previous observations that intestinal MIF concentrations are largely determined at the post translational level.
In an investigation of MIF as a biomarker of disease in IBD, the relationship between plasma MIF and endoscopic disease severity was investigated. The investigation found no correlation between plasma MIF and gold standard disease assessment, indicating that MIF has no value as a biomarker of disease.
The research group is continuing to investigate the biological properties of MIF in human disease, with particular emphasis on endogenous MIF control and the effect of MIF inhibition in vitro and in vivo. These investigations are timely given that international phase one trials are currently underway of a neutralizing anti-MIF antibody in human disease. Greater understanding of the contribution of MIF to IBD is urgently needed in order for patients with IBD to benefit from these advances