Recent advances on the roles of epidermal growth factor receptor in psoriasis

Abstract

Epidermal growth factor receptor (EGFR) is a well-characterized receptor tyrosine kinase that involved in many vital activities in cell development, such as cellular homeostasis, proliferation, division, differentiation and apoptosis. Natural activation of EGFR and the concomitant downstream signaling pathways regulation are substantial to maintain normal cellular functions. In recent studies, EGFR was demonstrated to be a fundamental modulator in the control of skin inflammatory responses. Several dermatologic diseases including psoriasis are related to the anomalous activation of EGFR signaling. It has been proved that the expression and activity of EGFR and its endogenous ligands are overexpressed in the active epidermis lesions of psoriasis. Moreover, the remarkable therapeutic improvement of chronic psoriasis in cancer patients during the treatment of EGFR inhibitors or anti-EGFR monoclonal antibodies are also recorded, suggesting that the EGFR-mediated signaling may conduct a crucial role in the pathophysiology of psoriasis.

Keywords: EGF; EGFR; keratinocytes; psoriasis.

Figure 1

Diagram of the ErbB signaling and trafficking pathways. Binding of specific ligands to the extracellular domain of ErbB receptors leads to receptor dimerization, tyrosine kinase activation and autophosphorylation (P). Thus the activated ErbB receptors induce different downstream signaling pathways and play different roles in biology. Meanwhile, ErbB receptors are recycled through endosome trafficking or degraded by late endosome and lysosome.

Figure 2

Effect of EGF receptor tyrosine kinase antagonist PD169540 on the histologic features of psoriatic lesion in skin organ culture. A, C, E: Psoriatic lesional skin from three patients without EGF-RTK antagonist. B, D, F: Psoriatic lesional skin treated with 1 μM EGF-RTK antagonist PD169540. HE. X89. G: Quantification of epidermal thickness. The thickness value of epidermal for antagonist-treated skin was significantly reduced compared to the untreated control (P<0.05).

Figure 3

1,25(OH)₂D₃ inhibits cell proliferation and the activation of EGFR in EGFR-overexpressing cells. NR6 (A) and HeLa (C) cells were incubated in the presence or absence of 100 nM 1,25(OH)₂D₃ for 48 h with or without 17 nM EGF for the final 24 h. Cell proliferation was measured by [³H]thymidine incorporation into DNA. NR6 (B) and HeLa (D) control cells or cells treated with 1,25(OH)₂D₃ were incubated with or without 17 nM EGF for 20 min at 37°C. Cellular extracts immunoprecipitated with anti-EGFR antibody and analyzed by Western blot for total EGFR and tyrosine-phosphorylated EGFR.

Figure 4

Improvement of psoriasis vulgaris in cancer patients after the treatment of anti-EGFR monoclonal antibody cetuximab. A: Manifestation of the raised, clearly demarcated, erythematous plaques covered with silvery-white lamellar scales before the treatment of cetuximab; B: Remarkably improvement of psoriasis skin lesions after initiation of cetuximab.