**6.2 Effects of methotrexate on endothelial cells**

T-cell migration from the intravascular space into the dermis is a crucial step in the pathogenesis of psoriasis, and this process is dependent on interactions between endothelial cells and T cells. Endothelial expression of appropriate adhesion ligands such as E-selectin and ICAM-1, are necessary for successful T-cell adhesion and migration [124, 139]. Studies have shown that MTX treatment firmly decreased the CLA, ICAM-1 and E-selectin expression in the endothelial cells [24]. Histologically, hypervascularity is noted in psoriatic skin, which contributes to the grossly observed erythema. When used at the high dosages necessary for chemotherapy, MTX is capable of inhibiting angiogenesis. MTX exerted its therapeutic effects in psoriasis by inhibiting angiogenesis.In 2003 Yamasaki et al. [140] found that MTX had an inhibitory effect on endothelial cell growth. Two years later, in 2005, Yazici et al. [25] employed immunohistochemistry on lesional skin biopsies to study the effects of MTX on angiogenesis, reporting a statistically significant decrease in the endothelial marker CD31 after treatment with MTX.

Dendritic cells (DCs) are considered as a key player in the pathogenesis of psoriasis. Interplay between DCs, T-cells and cytokine are main and complex in psoriasis. DCs are well recognized has antigen-presenting cells (APC) in the skin. Any modulation in APC interaction with other cells may significantly influence development of psoriatic lesions. Many studies has showed that MTX showed its immunomodulatory effect by suppressing APCs activity [141, 142]. Recently, the use of T-cell targeted therapy confirmed the critical role of lymphocytes [143]. On the other hand, the clinical phenotype observed in psoriasis is mostly accounted for by several alterations in epidermal KCs [144].
