A considerable number of interactions might also be indirect, mediated by a third partner

ents without such a history, and high SLEDAI score, high titer of anti-dsDNA antibodies, and low serum HDL were significantly associated with high plasma ADMA levels. These results suggest that patients with lupus are at high risk of developing cardiovascular diseases due to high plasma ADMA levels.145 In addition, it was reported that TNF- levels and other indices that reflect endothelial damage, such as sVCAM-1, were found to be elevated in lupus and other rheumatological conditions.146,147 Further support to the role of NO in rheumatological conditions is derived from previous studies where it was observed that drug-resistant Raynaud’s phenomenon in lupus responds to oral l-arginine therapy.148 That could be attributed to an increase in the generation of NO. These results are supported by the work of Fries et al,149 who showed that sildenafil, the NO donor, is of benefit in the management of Raynaud’s phenomenon. Increased production of IL-1, IL-6, TNF-, IFN-, MIF, and HMGB-1 attracts neutrophils, macrophages, and T-cells to initiate and perpetuate the inflammatory process by increasing the production of free radicals, eicosanoids, and cytokines in an autocrine fashion.1 IL-1 increases the production of endothelin-1 in cultured endothelial cells,150 and this contributes to vasospasm seen in lupus. Endothelial cells also produce PGI2 and NO, which are potent vasodilators and platelet antiaggregators and natural antagonists of endothelin-1. Hence, 153-18-4 enhancing the production of NO and/ or decreasing endothelin-1 and suppressing the production of proinflammatory molecules and enhancing the synthesis of anti-inflammatory molecules could be of significant benefit in lupus and other rheumatological conditions. In this context, it is interesting to note that recent studies have led to the identification of several newer methods of suppressing inappropriate generation of free radicals and proinflammatory cytokines, enhancing resolution of inflammation, and restoring immune balance and organ dysfunction to normal. Some of these strategies include immunosuppressive drugs such as FK-506, B-cell-targeted therapies, complement-component-targeted therapies, use of monoclonal antibodies against IFN-, glucoseinsulin infusion, administration of EP, lipid-enriched albumin, vagal nerve stimulation, and use of endogenous anti-inflammatory lipids such as LXs, resolvins, protectins, or their synthetic analogs along with their precursor PUFAs in combination with aspirin. These newer methods could be adopted in addition to the existing therapeutic modalities. A brief summary of these proposed newer therapeutic strategies is outlined below. FK-506 Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the immune system, thereby lowering the risk of organ rejection. It reduces IL-2 production by T-cells. It is also used in a topical PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19838485 preparation in the treatment of severe atopic dermatitis, severe refractory uveitis after bone marrow transplantation, and the skin condition vitiligo. It is a 23-membered macrolide lactone derived from the bacteria Streptomyces tsukubaensis. In T-cells, activation of the T-cell receptor increases intracellular calcium, which acts via calmodulin to activate calcineurin. That dephosphorylates the transcription factor NF-AT, which moves to the nucleus of the T-cell and increases the activity of gene coding for IL-2 and related cytokines. Tacrolimus prevents the dephosphor