Heme oxygenase (HO)-1 and its metabolic product carbon monoxide (CO) play regulatory roles in acute inflammatory states. In this study, we demonstrate that CO administration is effective as a therapeutic modality in mice with established chronic colitis. CO administration ameliorates chronic intestinal inflammation in a T helper (Th)1-mediated model of murine colitis, interleukin (IL)-10–deficient (IL-10 −/−) mice. In Th1-mediated inflammation, CO abrogates the synergistic effect of interferon (IFN)-γ on lipopolysaccharide-induced IL-12 p40 in murine macrophages and alters IFN-γ signaling by inhibiting a member of the IFN regulatory factor (IRF) family of transcription factors, IRF-8. A specific signaling pathway, not previously identified, is delineated that involves an obligatory role for HO-1 induction in the protection afforded by CO. Moreover, CO antagonizes the inhibitory effect of IFN-γ on HO-1 expression in macrophages. In macrophages and in Th1-mediated colitis, pharmacologic induction of HO-1 recapitulates the immunosuppressive effects of CO. In conclusion, this study begins to elucidate potential etiologic and therapeutic implications of CO and the HO-1 pathway in chronic inflammatory bowel diseases.

Interleukin (IL)-12 is a heterodimeric cytokine that is

Mast cells were discovered more than 100 years ago and until recently, have been considered renegades of the host with the sole purpose of perpetuating allergy. The discovery of mast cell-deficient mice that could be reconstituted with mast cells (the so called "mast cell knock-in" mice) has allowed the study of the in vivo functions of mast cells and revealed several new facets of these cells. It is now evident that mast cells have a much broader impact on many physiological and pathologic processes. Mast cells, particularly through their dynamic interaction with the nervous system, have been implicated in wound healing, tissue remodeling, and homeostasis. Perhaps the most progress has been made in our understanding of the role of mast cells in immunity outside the realm of allergy, and host defense. Mast cells play critical roles in both innate and adaptive immunity, including immune tolerance. Greater insight into mast cell biology has prompted studies probing the additional consequences of mast cell dysfunction, which reveal a central role for mast cells in the pathogenesis of autoimmune disorders, cardiovascular disorders, and cancer. Here, we review recent developments in the study of mast cells, which present a complex picture of mast cell functions.

Background and Aims-Innate immune responses are crucial for host defense against pathogens, but need to be tightly regulated to prevent chronic inflammation. Initial characterization of mice with a targeted inactivating mutation in the p110d subunit of phosphoinositide 3-kinase (PI3K p110δ D910A/D910A ) reveal defects in B-and T-cell signaling and chronic colitis. Here, we further characterize features of inflammatory bowel diseases (IBD) in these mice and investigate underlying innate immune defects.

Nuclear factor of activated T cells (NFAT) plays a critical role in the development and function of immune and non-immune cells. Although NFAT is a central transcriptional regulator of T cell cytokines, its role in macrophage specific gene expression is less defined. Previous work from our group demonstrated that NFAT regulates Il12b gene expression in macrophages. Here, we further investigate NFAT function in murine macrophages and determined the effects of a cell permeable NFAT inhibitor peptide 11R-VIVIT on experimental colitis in mice. Treatment of bone marrow derived macrophages (BMDMs) with tacrolimus or 11R-VIVIT significantly inhibited LPS and LPS plus IFN-γ induced IL-12 p40 mRNA and protein expression. IL-12 p70 and IL-23 secretion were also decreased. NFAT nuclear translocation and binding to the IL-12 p40 promoter was reduced by NFAT inhibition. Experiments in BMDMs from IL-10 deficient (Il10 −/−) mice demonstrate that inhibition of IL-12 expression by 11R-VIVIT was independent of IL-10 expression. To test its therapeutic potential, 11R-VIVIT was administered systemically to Il10 −/− mice with piroxicam-induced colitis. 11R-VIVIT treated mice demonstrated significant improvement in colitis compared to mice treated with an inactive peptide. Moreover, decreased spontaneous secretion of IL-12 p40 and TNF in supernatants from colon explant cultures was demonstrated. In summary, NFAT, widely recognized for its role in T cell biology, also regulates important innate inflammatory pathways in macrophages. Selective blocking of NFAT via a cell permeable inhibitory peptide is a promising therapeutic strategy for the treatment of inflammatory bowel diseases.