A Cell Permeable Peptide Inhibitor of NFAT Inhibits Macrophage Cytokine Expression and Ameliorates Experimental Colitis

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

Central serous chorioretinopathy: an update on pathogenesis and treatment

Central serous chorioretinopathy (CSC) is a chorioretinal disease, incompletely understood with systemic associations, a multifactorial aetiology, and a complex pathogenesis. Increased permeability from the choriocapillaris leads to focal or diffuse dysfunction of the retinal pigment epithelium causing a detachment of the neurosensory retina. CSC has been described in patients with endogenously high levels of corticosteroids as well as in patients with hypercortisolism due to the treatment of ocular or systemic diseases. It is therefore the only 'inflammatory' choroiditis, not proven to be associated with infection that is precipitated or worsened by glucocorticoids. Foveal attenuation, chronic macular oedema, and damage of the foveal photoreceptor layer have been reported as causes of visual loss in CSC. Photoreceptor atrophy in the fovea, despite successful retinal reattachment, typically occurs after a duration of symptoms of approximately 4 months. Treatment should therefore be considered after 3 months if there is angiographic evidence of ongoing foveal leakage in recurrent chronic CSC or in a single CSC episode accompanied by signs of chronic CSC alterations. Based on results of trials conducted so far, it appears that photodynamic therapy with verteporfin is effective and safer than argon laser treatment and should be considered as the treatment of choice, whereas micropulse diode laser photocoagulation seems to be an effective alternative. Glucocorticoid inhibitors are an interesting alternative treatment. Clinical trials are ongoing to test their efficacy. In addition, it is important, where possible, to discontinue any corticosteroid treatment. The possible association of CSC with stress should also be discussed with patients