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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]

Although salidroside and salidroside-like compounds are considered as most critical constitutes needed and responsible for multiple therapeutic benefits of Rhodiola rosea L., including anti-aging, direct demonstration regarding the role of salidroside in anti-aging process is still deficient. In this study, we selected the H(2)O(2)-induced premature senescence model in human fetal lung diploid fibroblasts to investigate the protection of salidroside against aging in vitro and associated molecular mechanisms. We found that salidroside considerably reversed senescence-like phenotypes in the oxidant challenged model, including alterations of morphology, cell cycle, SA-β-gal staining, DNA damage, as well as related molecules expression such as p53, p21 and p16. The protection occurred in a dose-dependent manner, with 5μM offering best efficacy. The proposed antioxidant property of the compound was confirmed in this cellular system, and thus at least partially accounted for the protection of the compound against premature senescence. Similar protection of salidroside against replicative senescence was observed as well. Interestingly, the regulation of senescence-related molecules by salidroside involved ROS-irrelevant mechanisms in both models. This finding presents salidroside as an attractive agent with potential to retard aging and attenuate age-related diseases in humans., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: To investigate the protective effects of putative AGEs (advanced glycation endproducts) inhibitor salidroside against aging in an accelerated mouse aging model induced by D-galactose., Methods: A group of 5-month-old C57BL/6J mice were treated daily with D-galactose, D-galactose combined with salidroside, salidroside alone, and control buffer for 8 weeks. At the end of the treatment, serum AGEs levels, neurological activities, expression of glial fibrillary acidic protein (GFAP) and neurotrophin-3 (NT-3) in the cerebral cortex, as well as lymphocyte proliferation and IL-2 production were determined., Results: D-galactose induced mouse aging model was developed as described before. As expected, salidroside blocked D-galactose induced increase of serum AGEs levels. It also reversed D-galactose induced aging effects in neural and immune system, as evidenced by improving motor activity, increasing memory latency time, and enhancing lymphocyte mitogenesis and interleukin-2 (IL-2) production. Furthermore, elevated expression of GFAP and NT-3 in the aged model mice was also reduced upon salidroside treatment., Conclusion: Salidroside inhibits AGEs formation in vivo, which at least partially contributes to its anti-aging effect in D-galactose induced aging model.

Objective: The roles of the transmembrane and secreted forms of tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) remain unclear. Agents used to inhibit TNFalpha have shown varying efficacy in RA patients, suggesting that anti-TNFalpha agents possess dissimilar mechanisms of action, including the ability to neutralize transmembrane (tmTNFalpha) and secreted TNFalpha. In this study, TNFalpha-knockout (TNFalpha-KO) mice that were genetically altered to express elevated levels of tmTNFalpha were constructed to further understand the roles of the 17-kd secreted, trimeric, and 26-kd transmembrane forms of TNFalpha., Methods: A speed-congenic mating scheme was used to generate 3 unique strains of mice: 1) transgenic tmTgA86 mice overexpressing 26-kd tmTNFalpha and also secreting 17-kd trimeric TNFalpha (tmTNFalpha-transgenic), 2) TNFalpha-/- mice (TNFalpha-KO), and 3) transgenic mice overexpressing tmTNFalpha backcrossed to TNFalpha-KO mice (tmTNFalpha-transgenic/TNFalpha-KO). Mice were treated with phosphate buffered saline (as vehicle control), dexamethasone (as positive control), or modified recombinant human soluble TNF receptor (sTNFR) p55 or p75, and were assessed clinically and histopathologically for signs of inflammation and development of arthritis., Results: The tmTNFalpha-transgenic/TNFalpha-KO mice were born with crinkled tails and spinal deformities similar to those in ankylosing spondylitis. By 2-4 weeks, these mice developed symmetric inflammatory arthritis, characterized by tissue swelling, pannus formation, and bone deformities. The tmTNFalpha-transgenic mice also developed spontaneous-onset arthritis, but at a slower rate (100% incidence by 10-12 weeks). Clinical and histologic progression of arthritis in the tmTNFalpha-transgenic/TNFalpha-KO mice was reduced by treatment with dexamethasone or with the p55 or p75 sTNFR (69% and 63% reduction in total histologic score, respectively)., Conclusion: These data show that arthritis is sufficiently initiated and maintained in tmTNFalpha-transgenic/TNFalpha-KO mice, and that it can be neutralized by recombinant human p55 or p75 sTNFR, resulting in amelioration of the biologic and subsequent histologic destructive effects of tmTNFalpha.

The pleiotropic functions of tumor necrosis factor-alpha (TNFalpha) 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 TNFalpha 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 TNFalpha is present in resting T cells. Initiation of splicing of TNFalpha pre-mRNA to mature mRNA requires T cell activation, which is unique and necessary for TNFalpha production when compared to its production in mononuclear phagocytes, including different lineages of macrophages (Mvarphi) and dendritic cells (DC). In this study, we further demonstrate that resting mouse B cells also contain pre-existing TNFalpha 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 TNFalpha mRNA splicing in vitro. The kinetic response of TNFalpha 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 TNFalpha splicing upon stimulation through the BCR. These studies demonstrate that the production of TNFalpha in activated B cells is regulated differently than in activated T cells, and these differences may allow for the selective inhibition of TNFalpha in various autoimmune diseases depending on the mechanism of action of the selected anti-TNFalpha therapy.