*7.1.3 Interferon-γ*

IFN-γ is believed to be an important mediator in psoriasis. Accumulated evidence from both in vivo and in vitro studies show that IFN-γ is a critical element in the induction of KC hyperproliferation in psoriasis [172, 181]. Abdallah et al. [182] showed that serum IFN-γ is a psoriasis severity and prognostic marker.

Some authors showed that serum IFN-γ levels in psoriatic patients were 15-fold and in blister fluid 17-fold higher than those in the control group. They correlated with the clinical severity of psoriasis expressed as PASI score [183–186]. In lesional skin, expression of IFN-γ is induced by some cytokines like IL-12, IL-18, and IL-23 are termed as IFN-γ stimulator [187]. Apart from above said stimulator, IL-7 also indirectly increased IFN-γ levels in both the psoriatic skin and serum of psoriatic patients. Inflammatory mediator IL-7 interact with both IL-2 and IL-12, which indirectly induced the synthesis of IFN-γ in psoriatic skin [188].

#### *Immunomodulatory Effect of Methotrexate Abruptly Controls Keratinocyte Activation in Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102811*

MTX treatment effectively reduced IFN-γ levels in serum and skin biopsy of psoriatic patients. This may due to the action of MTX on reducing serum IL-7 levels and is found to correlate with disease in RA patients [20]. Similar to this result, studies have shown that MTX decreases the expression of IFN-γ in RA patients [135, 136]. Adenosine or adenosine receptor agonists inhibit production of IFN-γ [130]. In 1990, Nesher and Moore [189] proposed that MTX might inhibit polyamine synthesis in monocytes, thereby polyamines failed to restore IFN-γ production.

As we discussed earlier in this chapter about the MTX action on T cell cytolysis, the same concept is applicable in this mechanism. The primary source of activated T cell is IFN-γ [127]. MTX induce the cytolysis of activated T-cell which directly reduced the IFN-γ in psoriasis. Invitro studies showed that inhibition of NFκB led to the complete blockade of extracellular IL-17A, IL-22, IFN-γ, and TNF-α production in CD4+ cells [190]. It is well known that MTX directly inhibit NFκB [191]. Thus, MTX declines IFN-γ levels by inhibiting NFκB in psoriatic skin which control the hyperproliferation of KCs.

## *7.1.4 Transforming growth factor-β1*

In the skin, TGF-β has been found to inhibit the growth of KCs but stimulate the growth of fibroblasts [192]. Plasma TGF-β1 is considered as a biomarker of psoriasis activity and treatment efficacy [193].

Gene and protein expression of TGF-β1 in lesional skin biopsies was found to be reduced compared to nonlesional skin biopsies [35, 97, 193]. Reduction in TGF-β1 in psoriasis may be due to increase in activated Akt levels. Activated Akt inhibit the phosphorylation of Smad2/3, is essential for TGF-β1 production [194, 195]. IFN-γ and NF-kappaB induces the expression of Smad7, an antagonistic Smad, which prevents the interaction of Smad3 with the TGF-β receptor [196, 197] leading to TGF-β1 production. Other factors that can suppress TGF-β1 productions are Th1 cytokines like TNF-α, IL-1, IL-6 [196]. All these factors could have lead to reduction in TGF-β1 levels in psoriasis. Reduction in TGF-β1 leads to increase in proliferation of KCs in psoriasis. Adhesiveness of T lymphocytes to dermal microvascular endothelial cells can be blocked by TGF-β1, so reduction of its expression and function may contribute to lymphocyte infiltration into psoriatic plaques [198].

MTX treatment causes overexpression of protein and mRNA level of TGF-β1 in lesional skin biopsy. Possible mechanism of MTX is accompanied by decreasing Ras methylation in psoriasis. This hypomethylation is accompanied by a mislocalization of Ras to the cytosol and a 4-fold decrease in the activation of Akt [199]. Decrease in Akt may lead to Smad 3 activation, which in turn increase TGF-β1 expression. Also MTX reduces Th1 cytokines like IL-1, IFN-γ, TNF-α, IL-6 [111, 135, 136, 188] which may lead to increase in TGF-β1 expression. Increase in TGF-β1 expression induced inhibition of KCs and is characterized by reversible retention of proliferation, or stopping of cell division cycle in the G1 phase [96]. Moreover, TGF-β causes transcriptional induction of K5 and K14 keratin genes [81]. Thus, TGF-β promotes the basal cell phenotype in stratified epithelia such as the epidermis, and that the effects of TGF-β are not anti-proliferative, but merely anti-hyperproliferative [78].

#### **7.2 Keratin changes in psoriatic skin after MTX action**

The pathogenesis of psoriasis is mainly depend on KCs and immune cells interaction. These interaction causes changes in the epidermal layers which destined the healthy skin to lesional psoriatic skin is critical one. Due to the epidermal change, acanthosis is caused by disruption in the transition of KC to anucleate corneocytes. This disrupts transition leads to hyperproliferation and immatured differentiation of KC in psoriasis. Thus, an alternate or regenerative pathway is activated by abnormal immune response along with abnormal keratins in psoriatic epidermis [200].
