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Monocytes/macrophages displaying different markers of activation/differentiation infiltrate the inflamed gut of patients with inflammatory bowel diseases (IBD), but the role that each monocyte/macrophage subpopulation plays in the pathogenesis of IBD is not fully understood. The hemoglobin scavenger receptor CD163, a specific marker of monocytes/macrophages, has been associated with either anti-inflammatory or inflammatory functions of macrophages in several pathologies. In this study we examined the tissue distribution and function of CD163-expressing monocytes/macrophages in IBD. CD163 RNA and protein expression was more pronounced in IBD in comparison to normal controls, with no significant difference between Crohn's disease and Ulcerative colitis. In IBD, over-expression of CD163 was restricted to areas with active inflammation and not influenced by current therapy. Immunohistochemical analysis confirmed the accumulation of CD163-expressing cells in IBD, mostly around and inside blood vessels, thus suggesting that these cells are partly recruited from the systemic circulation. Indeed, FACS analysis of circulating mononuclear cells showed that the fractions of CD163-positive monocytes were increased in IBD patients as compared to controls. Functionally, interleukin-6 up-regulated CD163 expression in lamina propria mononuclear cells and mucosal explants of normal subjects. In IBD blood and mucosal cell cultures, cross-linking of CD163 with a specific monoclonal anti-CD163 antibody enhanced tumor necrosis factor-α synthesis. These findings indicate that IBD mucosa is abundantly infiltrated with CD163-positive cells, which could contribute to amplify the inflammatory cytokine response.

Interleukin-25 (IL-25) plays a key role in the initiation and expansion of T helper (Th) 2 cell-mediated immune responses, thereby contributing to allergic diseases and host defense against helminthic parasites. More recent studies have however shown that IL-25 can also control the function of non-T cells, such as antigen presenting cells and endothelial cells, and reduces Th1/Th17-mediated pathologies. These new and exciting observations reveal a broader role for IL-25 than previously anticipated, and delineate various scenarios where therapeutic interventions around IL-25 activity can be imagined.

Over the last 15 years, the use of various biological therapies has largely improved the way we manage patients with Inflammatory Bowel Diseases (IBDs). Blockade of cytokine synthesis and/or activity is at the forefront of this new era with the success of inhibitors of tumor necrosis factor (TNF)-α. These therapies are however not effective in all IBD patients and efficacy may wane. Moreover, patients treated with anti-TNF-α antibodies can develop severe side-effects and new immune-mediated diseases. Therefore, a new challenge is to elucidate new inflammatory networks in the IBD tissue and develop novel anti-cytokine compounds, which may act in patients who are resistant to or cannot receive anti-TNF-α therapies. In this article we review the available data supporting the pathogenic role of IL-23 and Th17-related cytokines in IBD, and discuss whether and how compounds that control the activity of these cytokines may enter into the therapeutic armamentarium of IBD.