**6. Metabolic activity of methoxerate on psorisis**

MTX mechanisms of action are likely to account for its antiproliferative and immunosuppressive effects [122, 123]. The key feature of psoriasis is KC hyperproliferation. MTX was found to induce maturation and inhibition of KC proliferation through its metabolic action of kerationocyte. The putative effects of MTX are listed below:


#### **6.1 Effect of methotrexate on T cells**

Evidence supports that activated T cells are key players in the immunopathogenesis of psoriasis. The following components involving T cells are considered crucial in the pathogenesis of psoriasis. Activated endothelium of psoriatic skin has shown adhesion molecules like E-selectin, CLA, ICAM-1 and ICAM-3, which promoted the activation of KCs and T-cells in psoriasis. Study by Sigmundsdottir et al. showed that treatment of 5−25 mg of MTX in 16 moderate to severe psoriasis patients has showed decreased E-selectin and CLA expression in psoriatic skin. Thus, the downregulation of peripheral Tcell-adhesion interaction by MTX in psoriasis patients implies its therapeutic action on psoriatic skin lesion [124]. Invitro flowcytometric and immunohistochemistry studies have shown that peripheral T cells were found to show less interaction with CLA and ICAM-1 after MTX administration 10−9 M to 10−5 M for 5 days. Follow-up experiments revealed that MTX suppression of CLA expression could be reversed by folinic acid (leucovorin) supplementation [123].

MTX has also target T cell by inducing cytolysis. Some studies has shown that MTX induce Tcell apoptosis in more sensitive manner [125–127]. MTX may induce cell death via free radical oxygen species. Phillips et al. [126] inhibited MTX induced T-cell death with the addition of the antioxidant glutathione and its precursor, Nacetylcysteine. Accumulating evidence suggests that MTX alters T-cell production of several cytokines, including IL-1, IL-2, IL-4, IL-8, INF-γ and TNF-α [128–131]. As a key element in psoriasis pathogenesis, the cytokine TNF-α was found at higher levels in psoriasis plaques and the synovial fluid of patients with psoriatic arthritis [129, 132, 133]. Associations

between MTX and TNF-α levels have been observed since the 1990s. Studies by Seitz et al. [132], Neurath et al. [134] and Hildner et al. [135] found that MTX had reduced TNF-α production in the peripheral blood mononuclear cells (PBMCs) of psoriasis patients.

Action of MTX on reducing serum and synovial TNF-α has been widely established in both Psoriasis and rheumatoid arthritis patients showed its immunomodulatory effects [136–138]. Based on the stage and route of T-cell activation, it has been evident that MTX inhibits T-cell TNF-α production [129, 130, 135]. These all findings suggest that MTX can diminish TNF-α produced by activated T cells showed its immunomodulatory action.
