Epidermal growth factor receptor tyrosine kinase inhibitors induce CCL2 and CCL5 via reduction in IL-1R2 in keratinocytes

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) is a transducer of mitogenic signals, and is involved in the pathogenesis and progression of a number of cancers, including non-small cell lung cancer (NSCLC). Gefitinib is an EGFR-TK inhibitor that is clinically used to treat NSCLC; however, this drug frequently causes adverse effects, including skin eruptions. The mechanism underlying these skin reactions is elusive, although it is assumed that they are caused by the inhibition of EGFR-TK signalling in epidermal and adnexal cells. In this article, we demonstrate by immunocytochemistry that the skin lesions of patients treated with oral gefitinib had higher expression of CCL2 and CCL5 compared to normal human epidermis. Further, PD153035, a gefitinib prototype, induced CCL2 and CCL5 mRNA and protein expression in HaCaT and HSC-1 keratinocyte cell lines with or without interleukin-1 (IL-1) treatment in vitro. PD153035 also reduced the levels of interleukin-1 receptor 2 (IL-1R2), an IL-1 decoy receptor. Moreover, we demonstrate that reduction in IL-1R2 by RNA interference increased IL-1-mediated CCL2 and CCL5 mRNA and protein expression. Taken together, our data strongly suggest that IL-1-mediated signalling is activated to induce the high expression of CCL2 and CCL5 via reduction in IL-1R2 in the skin lesions caused by gefitinib.