*7.1.2 Tumor necrosis factor alpha*

TNF-α is a pivotal proinflammatory cytokine of the innate immune response and a key for skin inflammation [175]. TNF-α induce the expression of adhesion molecule ICAM-1 on KC through the mediation of p55 and ICAM-1 induces the infiltration of MNCs in the dermis, which promotes the development and progression of psoriasis vulgaris [176]. Thereby it causes hyperproliferation in psoriasis.

Many studies have shown that plasma concentration of TNF-α was significantly higher in psoriatic patients compared to the control group [35, 177, 178]. Johansen [179] showed increased TNF-α protein expression, but similar TNF-α mRNA levels, in lesional compared with nonlesional psoriatic skin, this results showed that TNF-α is regulated posttranscriptionally. Increased activation of MAPK-activated protein kinase 2 (MK2) is responsible for the elevated and posttranscriptionally regulated TNF-α protein expression in psoriatic skin. IL-1 β also amplified TNF-α protein expression by causing activation of p38 MAPK and MK2.

Action of MTX to overwhelm TNF activity is by suppressing TNF-induced nuclear factor-κB activation in vitro, in part related to a reduction in the degradation and inactivation of an inhibitor of this factor, IκBα, and probably related to the release of adenosine [180]. Gerards et al. [130] showed that Adenosine or adenosine receptor agonists inhibit production of TNF-α. MTX reduces TNF-α level and also reduces the adhesion molecules like E-selctin and ICAM-1, thereby it reduces TNF-α induced hyperproliferation in psoriasis. Decrease in TNF-α by MTX shows its anti-proliferative and anti-inflammatory effects.
