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Abstract: Tissue-selective recruitment of immunocytes to cutaneous tissues, a complex multistep cascade mediated by a large variety of cytokines, chemokines, and adhesion molecules, is thought to be a pivotal process in the pathogenesis of psoriasis. Following this notion, specifically targeting leukocyte trafficking remains an attractive approach for the treatment of psoriasis. It is increasingly recognized that during the pathogenesis of psoriasis not only effector T cells play important roles, but also multiple interactions between T cells, dendritic cells, macrophages, mast cells, endothelial cells, and keratinocytes are crucial for the full-fledged development of psoriasis. Meanwhile, the first biologics specifically inhibiting key molecules involved in cutaneous leukocyte recruitment have been approved for the treatment of psoriasis. It is, however, challenging to predict that molecules in this complex process with many redundant and/or functionally overlapping players will suffice as therapeutic targets. In this review, we will discuss the molecules and mechanisms involved in trafficking of different types of leukocytes and elucidate modes of action as well as therapeutic strategies of existing drugs and drug candidates. [Copyright &y& Elsevier]

Abstract: Proinflammatory cytokines such as TNFα and IL-1β are produced in lesional skin of chronic plaque psoriasis patients, and at other sites of chronic inflammation such as arthritic joints. They play vital roles in maintaining inflammation. It has recently been suggested that activated T cell contact-mediated monocyte activation, leading to the production of proinflammatory cytokines, contributes to the pathogenesis of psoriasis and other chronic inflammatory diseases such as psoriatic arthritis and rheumatoid arthritis. Using a T cell membrane–monocyte contact bioassay, we have identified small molecule antagonists that differentially block anti-CD3/anti-CD28 activated T cell-mediated, but not LPS-stimulated, TNFα production from monocytes. We selected several kinase inhibitors from the Berlex/Schering kinase library and tested the effect of these compounds in blocking TNFα production in the T cell membrane–monocyte contact bioassay. We have demonstrated that one compound BLX-1, from a p38 MAP kinase inhibitor project, inhibited T cell-mediated TNFα production from monocytes by about 80%, without any effect on TNFα production from LPS-stimulated monocytes. Other BLX-1 analogs showed 32–83% inhibition of TNFα production with LPS stimulation as compared to almost 100% inhibition of T cell-mediated TNFα production. In contrast, PKC inhibitors BLX-5, Go6983, and Ro-31-8220, inhibited TNFα production from both activated T cell membrane- and LPS-stimulated monocytes to the same extent (in the range of 50–100% inhibition). Therefore, the activated T cell membrane–monocyte contact bioassay can be used to screen small molecule antagonists that specifically target adaptive but not LPS-mediated innate immunity. Small molecule TNFα inhibitors interfering specifically with activated T cell contact-mediated TNFα production from monocytes, but not with LPS-mediated TNFα production of myeloid cells, are predicted to have an improved side-effect profile and thus may provide more favorable therapeutics for the treatment of T cell-mediated inflammatory diseases. [Copyright &y& Elsevier]

Abstract: The pleiotropic functions of tumor necrosis factor-alpha (TNFα) have brought considerable attention in the past decade to its physiological and pathological roles in inflammatory and autoimmune diseases. However, little is known about how the production of TNFα is regulated at the transcriptional and translational levels in immune cells such as T and B lymphocytes. Our previous study demonstrated that unspliced “pre-mRNA” of TNFα is present in resting T cells. Initiation of splicing of TNFα pre-mRNA to mature mRNA requires T cell activation, which is unique and necessary for TNFα production when compared to its production in mononuclear phagocytes, including different lineages of macrophages (Mϕ) and dendritic cells (DC). In this study, we further demonstrate that resting mouse B cells also contain pre-existing TNFα mRNA. The physiological process of B cell activation induced by (1) either the cross-linking of the B cell receptor (BCR) or CD40, (2) treatment with LPS, or PMA plus ionomycin, induces TNFα mRNA splicing in vitro. The kinetic response of TNFα splicing in B cells is much slower when compared to that in activated T cells. Studies using well-known kinase inhibitors demonstrated that MAP kinase kinase (MEK) and protein kinase C (PKC) are required for TNFα splicing upon stimulation through the BCR. These studies demonstrate that the production of TNFα in activated B cells is regulated differently than in activated T cells, and these differences may allow for the selective inhibition of TNFα in various autoimmune diseases depending on the mechanism of action of the selected anti-TNFα therapy. [Copyright &y& Elsevier]