**7.1 Activation and deactivation signals of KAC**

In psoriasis, KCs undergo activation pathway. This activation process is governed by growth factors and cytokines, such IL-1, TNF-α, IFN-γ and TGF-β [78].

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

#### *7.1.1 Interleukin-1*

IL-1 is likely to be an important mediator in the initiation and maintenance of psoriatic plaques and may represent an attractive therapeutic target [152].

#### *7.1.1.1 Interleukin-1 alpha*

Our studies in IL-l α levels and its action in psoriasis had clearly showed that IL-l α level is reduced in psoriatic skin as well as in plasma [153], which was further supported by several studies [154–157]. Mechanism behind this reduction is mainly depend on the upstream level of nerve growth factor, a IL-1 α down-regulator [158, 159] in psoriasis.

The second messenger cyclic adenosine monophosphate (cAMP) has been regarded as a regulator for cell growth and proliferation [160]. The action of IL-l α is mainly depends on its phosphorylation by cyclic cAMP-dependent protein kinase. Thus, phosphorylation converts it into active form and enhanced its susceptibility to tryptic digestion, which may allow its release into the extracellular milieu [161]. Reduced cAMP levels has been reported in psoriasis [162]. This also could lead to reduced IL-l α levels in lesional skin biopsies.

Studies showed that MTX significantly increased IL-l α levels in plasma and skin biopsies of psoriasis patients. This may due to increase in the levels of cAMP by MTX through adenosine release [153, 163] and that led to an increase in IL-1 α level.

#### *7.1.1.2 Interleukin-1 beta and caspase-1*

Many studies have reported the importance of IL-1 β and caspase-1 (IL-1 β converting enzyme) in pathogenesis of psoriasis [153, 156, 157, 164]. Increased expression of IL-1 β in psoriatic epidermal cells, related to the activated KC-immunocyte in psoriasis. Psoriatic plaques express increased IL-1 β mRNA relative to non-lesional skin [161]. IL-1 β has been shown to induce the expression of adhesion molecules on various cell types and contributes to inflammatory responses. Activation of ERK, JNK, AP-1, and NFκB are leads to IL-1 β-induced ICAM-1 expression and leukocyte adhesion [165], thereby increase in ICAM-1 cause hyperproliferation of KC in psoriasis.

Normal KCs do not contain a biologically active form of caspases-1 [166], whereas in psoriatic epidermis, caspase-5 act as an upstream activator of caspase-1 [167]. Caspase-5 mRNA is induced by IFN-γ in vitro in both KCs and PBMCs and that this induction is most likely mediated through the NFκB pathway [168].

Mizutani et al. [169] found that IL-1 β levels in PBMC of psoriatic patients were decreased after 2 weeks of MTX treatment, due to suppression of KC paracrine system by MTX. Also, MTX effectively reduced IL-1 β levels in plasma and skin biopsies of psoriasis patients [153]. There are two possible mechanism of MTX decrease IL-1 β is elucidated above. One is direct mechanism and another one is indirect mechanism. The direct mechanism is as follows: MTX treatment inhibits the enzyme5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase (ATIC), which leads to accumulation of the substrate AICAR. The increased AICAR inhibit the enzymes, AMP deaminase and adenosine deaminase, which are essential for the catabolism of AMP and adenosine. This inhibitory action eventually increased adenosine in circulation. Thus, increased extracellular adenosine firmly increased cAMP in skin which finally inhibits the production of proinflammatory cytokine IL-1 β [163].

The indirect mechanism of MTX on reducing IL-1 β levels in psoriasis is mainly depend on reduction of infiltration of lymphocytes and monocytes in psoriatic dermis [162, 170]. MTX also decreased g the circulating and systemic levels of IL-1 β, by blocking the binding of IL-1 β to its respective receptor on monocytes, lymphocytes and granulocytes [171]. Studies have shown that IL-l α down-regulates IL-1 β via prostaglandin E2 synthesis [172]. Therefore increase in IL-1 α levels by MTX, definitely downregulates IL-1 β by above said mechanisms. Another mechanisms of MTX reduced IL-1 β, its action on caspase-1 expression in lesional skin biopsy. This may due to IFN-γ reduction by MTX [173, 174], which leads to decrease in caspase-5 expression that causes reduction in caspase-1 expression.
