Mitogen-activated protein kinase (MAPK) regulates leukotriene D4-induced HB-EGF and ADAM12 expression in human airway smooth muscle cells.

Fumio Kumasawa, Shu Hashimoto, Kenji Mizumura, Ikuko Takeshita, Akira Onose, Itsuro Jibiki, Shuichiro Maruoka, Yasuhiro Gon, Tomoko Kobayashi, Noriaki Takahashi

Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.

Asian Pacific journal of allergy and immunology / launched by the Allergy and Immunology Society of Thailand 2013 Mar

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Cysteinyl leukotriene (LT) induces bronchoconstriction as well as airway inflammation and remodeling. Heparin-binding EGF-like growth factor (HB-EGF) is associated with remodeling in airway smooth muscle (ASM) cells in bronchial asthma. A disintegrin and metalloproteinase (ADAM) 12 is an enzyme implicated in the ectodomain shedding of membrane-anchored proHB-EGF and release of HB-EGF. To determine the role of LTD4 in HB-EGF and ADAM12 expression and the regulatory mechanism in human ASM cells, we analyzed a functioning signaling molecule in LTD4-induced HB-EGF and ADAM12 expression in human ASM cells by focusing on the role of mitogen-activated protein kinase (MAPK) cascades. Human ASM cells were stimulated LTD4 in a time-dependent manner. We observed phosphorylation of MAPK by western blot analysis and the expression of HB-EGF and ADAM12 by quantitative PCR analysis of mRNA. Furthermore, we pretreated with specific inhibitors of MAPK and LTD4. LTD4 induced an extracellular-signal regulated kinase (ERK), p38 MAPK and c-Jun-NH2-terminal kinase (JNK) phosphorylation in human ASM cells. LTD4 induced HB-EGF and ADAM12 mRNA expression. Furthermore, the regulation of LTD4-induced HB-EGF and ADAM12 mRNA expression is associated with ERK and p38 MAPK, not but JNK. we conclude that p38 MAPK and ERK are capable of regulating LTD4-induced HB-EGF and ADAM12 expression in human ASM cells. In bronchial asthma, the specific inhibitor of p38 MAPK and ERK may produce beneficial effects in controlling airway remodeling and inflammation.

Citation

Fumio Kumasawa, Shu Hashimoto, Kenji Mizumura, Ikuko Takeshita, Akira Onose, Itsuro Jibiki, Shuichiro Maruoka, Yasuhiro Gon, Tomoko Kobayashi, Noriaki Takahashi. Mitogen-activated protein kinase (MAPK) regulates leukotriene D4-induced HB-EGF and ADAM12 expression in human airway smooth muscle cells. Asian Pacific journal of allergy and immunology / launched by the Allergy and Immunology Society of Thailand. 2013 Mar;31(1):58-66