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A putative anti-inflammatory role for TRPM8 in IBS 113 5 Discussion Here, we provide preliminary findings in support for TRPM8 as a potential anti- inflammatory mediator in IBS patients. Increased TRPM8-IR on dendritic cells within the colonic mucosa coupled with decreased release of cytokines begins to delineate the potential cellular mechanisms underlying the therapeutic benefit of TRPM8 agonists, such as L-menthol in peppermint oil. Decreased release of cytokines IL-1 β , IL-6, and TNF- α from DCs by TRPM8 stimulation is important as their respective receptors are expressed on colonic visceral afferents that mediate pain generation. 18 Indeed, peripheral blood mononuclear cells (PBMC) isolated from IBS patients secrete increased levels of these same cytokines, IL-1 β , IL-6, and TNF- α , compared to healthy controls. 18 In addition, TRPM8-IR CD103+ DCs may also interact with CGRP-IR sensory neurons that are in close apposition, possibly by neuro-immune communications where CGRP inhibits cytokine release from dendritic cells as demonstrated in mice. 13 Considering that we observed increased mRNA expression and TRPM8-IR (which appears to colocalize with immune cells) in IBS, we postulate that this represents an inducible counterregulatory anti-inflammatory mechanism. This mechanism is potentially related to the severity of pain symptoms, as we also observed a positive association between TRPM8 mRNA expression and pain scores. This is supported by data demonstrating increased pain scores associated with elevated levels of inflammatory cytokines in IBS- diarrhoea patients. 18 There is growing (albeit inconclusive) evidence that an inflammatory response is likely to contribute to pain symptoms in IBS patients through low-grade inflammation in a similar manner to IBD patients suggesting a commonality in pain mechanisms via neuro-immune mechanisms, with IBS-D patients having increased levels of IL-8 and IL-1. 19-22 In mice, colonic visceral afferents express receptors for the cytokines, IL-1 β , IL-6, TNF- α and IL-10, and visceral hypersensitivity is induced by these cytokines in electrophysiology experiments. 18-22 Indeed, peripheral blood mononuclear cells (PBMC) isolated from IBS patients secrete increased levels of these same cytokines, IL-1 β , IL-6, and TNF- α , compared to healthy controls. 18 Human visceral afferents have the capacity to respond to numerous inflammatory mediators 23-24 and are likely similarly responsive directly to cytokines. This is a mechanism that requires further detailed exploration but is supported by the studies presented here demonstrating close apposition of sensory nerve endings and immune cells. In addition, the observed regional differences in TRPM8 mRNA expression (proximal colon higher compared to distal colon) may also provide an explanation for the phenomenon that the clinical efficacy of peppermint oil also depends on the release profile of its formulation. 5