*7.2.2 Keratin 10*

When mitotically active basal epidermal KCs withdrawn from the cell cycle are committed to terminal differentiation, they switch off K14 expression and induce the expression of K10 [27]. K10 are the major structural proteins of the epidermis and belong to the large family of IF proteins [29, 41, 42]. K10 is also involved in the control of cell proliferation [43]. Decreased K10 protein and gene expression were observed in lesional psoriatic skin biospies [33–35]. Subsequently, hyperproliferation of KCs in psoriasis is mainly depend on the expression of K10. The possible mechanism is as follows, decrease in differentiation marker K10 leads to increased phosphorylation of Rb protein, which leads to increased epidermal cell cycle proteins, Cyclin D and E. The increased epidermal cell cycle proteins activate the phosphorylation of antiapoptotic protein Akt. Thus activation of Akt by decreased K10 leads to hyperproliferation of KCs in psoriasis [52].

E-cadherin is specific markers expressed in the endothelial cells are important for differentiation process. MTX promptly increased E-cadherin expression [201] which deliberately causes extracellular calcium concentration-dependent KC differentiation by increasing K10 in psoriatic skin. IL-22 which is considered to have an inhibitory effect on the expression of K10 [205], is reduced by MTX in psoriasis patients [206]. Also MTX increase c-fos expression which activate AP-1 transcription factor regulates K10 expression [207]. Thus MTX action on K10 expression proves the controlled differentiation in psoriatic KC.

The main therapeutic action of MTX is inhibiting DNA methylation by interfering folate metabolism [207]. Studies have shown that inhibition of DNA methylation directly increased transcription of K10 gene [208]. This shows the therapeutic action of MTX on psoriatic skin.

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

#### *7.2.3 Keratin 16*

Keratin 16 expressions, reduces the fraction of cells in G1 while increasing that in S phase [53]. Many authors also shown an upregulation of K6 and K16 [33–35] in psoriatic epidermis. Action of MTX on reducing Keratin 16 protein and mRNA expression in lesional skin biopsies is interesting. Ras signaling is also induces K16 in psoriasis. The action of MTX in decreasing K16 level is depends on the enzyme isoprenylcysteine carboxyl methyltransferase (Icmt). Inhibition of Icmt by MTX, indicates the link between antifolates and Ras. Icmt inhibition leads to decrease in carboxyl methylation of Ras [199], which induces EGF. Induced EGF directly decreased K16 expression. Overall mechanism indicates the action of MTX on K16 reduction. Apart from this, MTX also inhibits the IL-1, TNF-α levels [135, 153, 169], which also might leads to decrease in K16 expression in psoriasis. All these leads to inhibition of cell proliferation in psoriasis. Decrease in Keratin 16 by MTX indicates the strong anti-proliferative effect of MTX.

### *7.2.4 Keratin K17*

Keratin K17, the myoepithelial keratin, which is not expressed in normal skin except for hair follicles, sweat and sebaceous glands and basal cells of the interfollicular epidermis in the scalp, is over-expressed in psoriatic epidermis [209, 210]. Keratin 17 is considered as a therapeutic target and marker of anti-psoriatic therapies used for the treatment of psoriasis [63, 64].

MTX substantially reduced abnormal K17 protein and gene expression in psoriasis by reducing circulatory inflammatory mediators like IL-22 [205] and IL-6 levels [111] in psoriasis patients. Many studies in Rheumatoid Arthritis patients showed that the production of IL-17 at the mRNA level and IFN-γ were reduced after MTX treatment [35, 135, 211]. Altogether MTX reduces K17 expression by decreasing IFN-γ inducers. Decrease in Keratin 17 by MTX indicates its therapeutic efficacy which helps to maintain the normal phenotype in KC.
