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

Mayuko Yamaki, Kazumitsu Sugiura, Yoshinao Muro, Yoshie Shimoyama, Yasushi Tomita

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)730-735
Number of pages6
JournalExperimental Dermatology
Volume19
Issue number8
DOIs
Publication statusPublished - 01-08-2010

Fingerprint

Interleukin-1 Receptors
Interleukin-1
Keratinocytes
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Skin
Non-Small Cell Lung Carcinoma
Cells
Skin effect
Messenger RNA
RNA Interference
Transducers
Epidermis
Proteins
Immunohistochemistry
RNA
Cell Line
gefitinib
Pharmaceutical Preparations
Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology

Cite this

Yamaki, Mayuko ; Sugiura, Kazumitsu ; Muro, Yoshinao ; Shimoyama, Yoshie ; Tomita, Yasushi. / Epidermal growth factor receptor tyrosine kinase inhibitors induce CCL2 and CCL5 via reduction in IL-1R2 in keratinocytes. In: Experimental Dermatology. 2010 ; Vol. 19, No. 8. pp. 730-735.
@article{08191563aab24c12a756754b2ff35fb4,
title = "Epidermal growth factor receptor tyrosine kinase inhibitors induce CCL2 and CCL5 via reduction in IL-1R2 in keratinocytes",
abstract = "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.",
author = "Mayuko Yamaki and Kazumitsu Sugiura and Yoshinao Muro and Yoshie Shimoyama and Yasushi Tomita",
year = "2010",
month = "8",
day = "1",
doi = "10.1111/j.1600-0625.2010.01108.x",
language = "English",
volume = "19",
pages = "730--735",
journal = "Experimental Dermatology",
issn = "0906-6705",
publisher = "Wiley-Blackwell",
number = "8",

}

Epidermal growth factor receptor tyrosine kinase inhibitors induce CCL2 and CCL5 via reduction in IL-1R2 in keratinocytes. / Yamaki, Mayuko; Sugiura, Kazumitsu; Muro, Yoshinao; Shimoyama, Yoshie; Tomita, Yasushi.

In: Experimental Dermatology, Vol. 19, No. 8, 01.08.2010, p. 730-735.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Epidermal growth factor receptor tyrosine kinase inhibitors induce CCL2 and CCL5 via reduction in IL-1R2 in keratinocytes

AU - Yamaki, Mayuko

AU - Sugiura, Kazumitsu

AU - Muro, Yoshinao

AU - Shimoyama, Yoshie

AU - Tomita, Yasushi

PY - 2010/8/1

Y1 - 2010/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77954841807&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954841807&partnerID=8YFLogxK

U2 - 10.1111/j.1600-0625.2010.01108.x

DO - 10.1111/j.1600-0625.2010.01108.x

M3 - Article

C2 - 20590818

AN - SCOPUS:77954841807

VL - 19

SP - 730

EP - 735

JO - Experimental Dermatology

JF - Experimental Dermatology

SN - 0906-6705

IS - 8

ER -