**2. Keratins involved in psoriasis**

The hyperproliferation seemed to result from an increase in the number of transit amplifying cells, following depletion of the stem cell compartment [9, 26]. The differentiation state of epidermal KCs is reflected by the intricate expression pattern of keratins [27, 28]. Keratins are members of the large IF gene family [29] in all epithelia including the epidermis. Basal KCs express keratins (K) K5 and K14, which helps to maintain epidermal shape are replaced by differentiation keratin K1 and K10 [27], whereas in activated KCs, keratins K6, K16, and Keratin 17 (K17), which are distinct

#### **Figure 2.**

*Protein structure of epidermal and hyperproliferative keratins protein. (a) Schematic representation of secondary structure of all four keratins with their domain and sub domain. Whereas, S = peptide epitope; L = linker. (b) Region specific of 33 deleterious mutation localization. The left sides of the figures are the 3D structure of all four keratins CDS region. The right sides of the figures are the 3D structures of domains with mutated residues. The mutated residues are numbered according to their position on regions. The position of mutated amino acids (aa) on all four keratins and on CDS regions are provided [31].*

from the keratins in the healthy epidermis, are expressed [30]. Therefore, keratins K6, K16, and K17 are usually referred to as activation- and hyperproliferation-associated keratins. There are predicted deleterious mutations were highly located in α-helical rod domain of keratins which forms coiled structure to these keratins, are important to maintain the structural integrity of the skin. Thus the genetic defects of basal keratin K14 and differentiation keratin K10 in skin might leads to express abnormal keratin pair which causes thickening of epidermis (acanthosis) in psoriasis (**Figure 2**).

### **2.1 Keratin 14**

Keratin 5 and K14 pair are considered as a biochemical marker of mitotically active basal layers. This pairs are supports to maintain epidermal integrity as well as protects skin from mechanical stress. Interestingly, the K5/K14 pair is expressed in the basal layer of the epidermis, which contains epidermal stem cells and transient amplifying (TA) cells [32]. Many studies have showed that the level of K14 was considerably higher in lesional skin than in normal epidermis [33–35]. p53 activation promotes the expression of p21 and the repression of K14 during epidermal differentiation [36], whereas in psoriasis, there is downregulation of p53 [37] and also decreased Notch 1 expression [38] causes increase in K14 expression in psoriasis [39]. p75NTR is nearly absent in psoriatic KCs that are reportedly resistant to apoptosis, leads to increase TA cell turnover in psoriasis which leads to increase in K14 expression in psoriasis (**Figure 3**) [40].

#### **2.2 Keratin 10**

The epidermis is a stratified epithelium that regenerates permanently from the basal layer. K10 pair with K1 is considered as a major differentiation keratin [29]. Normally,the basal layer contains K14, K15, and K5, whereas suprabasal, postmitotic *Immunomodulatory Effect of Methotrexate Abruptly Controls Keratinocyte Activation in Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102811*

#### **Figure 3.**

*Immunofluorescence analysis of keratins in control and lesional psoriatic skin. Immunofluorescence analysis of epidermal and hyperproliferative type I keratins in frozen skin sections from patients with psoriatic skin (×20 magnification, respectively), and nuclei were visualized with 4*′*-6-diamidino-2-phenylindole (DAPI). Bar = 100 μm. Ab = antibody [31].*

cells switch to the expression of K1 and K10 [41, 42] is also involved in the control of cell proliferation [43]. Many studies have shown a downregulation of K1 and K10 [33–35] in psoriatic epidermis. This may be due to downregulation in E-cadherin expression [43], and increase in IL-22 [45–48] levels in psoriasis. Also c-fos protein in AP-1 transcription factor highly regulates a number of genes that are involved in KC differentiation were found to be reduced in psoriasis [49–52].

In psoriasis, defects in K10 expression leads to hyperproliferation of KCs by decreasing its inhibitory action on Rb phosphorylation, which leads to increased Cyclin D and E expression and also increased Phosho-Akt levels in psoriasis (**Figure 3**) [52].

#### **2.3 Keratin 16**

Keratin 16 expressions, reduces the fraction of cells in G1 while increasing that in S phase [52]. Many authors also shown an upregulation of K6 and K16 [33, 35, 54, 55] in psoriatic epidermis. Decrease expression of keratin 10 gene leads to hyperproliferation of basal cells, alterations in epidermal cell cycle by inducing cmyc, cyclin D1, 14-3-3σ, keratin 6 and keratin 16 [56]. Multiple transcription factors activated by the extracellular signals revealed the specific signals transduction mechanisms that respond to the corresponding growth factors and cytokines. For example, interleukin-1 (IL-1), present in healthy epidermis in inactive form [57], when released autocrinely, activates NFκB and C/EBPβ, thus initiating KC activation. Among the characteristics of activated KCs is the production of tumor necrosis factor-α (TNF-α) [58], which maintains activated NFκB and C/EBPβ. Activated KCs produce ligands of the EGF receptor that cause activation of AP1, such as transforming growth factor-α (TGF-α), amphiregulin and HB-EGF. Interestingly, all these cytokines and

**Figure 4.** *Transcriptional regulation of the human keratin 16 gene in HaCaT cells.*

growth factors IL-1, TNF-α, TGF-α and EGF, induce expression of the K16 genes, albeit through separate pathways [54, 59–61]. Study has shown that biosynthesis of AP1 protein (c-Jun and c-Fos) through Ras activation are actively participate in the transcriptional regulation for EGF which induced keratin 16 gene expression in KCs [62], this implies that EGF induces Keratin 16 expression in psoriasis (**Figure 4**).
