The tyrosine phosphatase, SHP-1, is involved in bronchial mucin production during oxidative stress.
Mucus hypersecretion is a clinically important manifestation of chronic inflammatory airway diseases, such as asthma and Chronic obstructive pulmonary disease (COPD). Mucin production in airway epithelia is increased under conditions of oxidative stress. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 suppression is related to the development of airway inflammation and increased ROS levels. In this study, we investigated the role of SHP-1 in mucin secretion triggered by oxidative stress. Human lung mucoepidermoid H292 carcinoma cells were transfected with specific siRNA to eliminate SHP-1 gene expression. Cultured cells were treated with hydrogen peroxide (H(2)O(2)), and Mucin 5AC(MUC5AC) gene expression and mucin production were determined. Activation of p38 mitogen activated protein kinase (MAPK) in association with MUC5AC production was evaluated. N-acetylcysteine (NAC) was employed to determine whether antioxidants could block MUC5AC production. To establish the precise role of p38, mucin expression was observed after pre-treatment of SHP-1-depleted H292 cells with the p38 chemical blocker. We investigated the in vivo effects of oxidative stress on airway mucus production in SHP-1-deficient heterozygous (mev/+) mice. MUC5AC expression was enhanced in SHP-1 knockdown H292 cells exposed to H(2)O(2), compared to that in control cells. The ratio between phosphorylated and total p38 was significantly increased in SHP-1-deficient cells under oxidative stress. Pre-treatment with NAC suppressed both MUC5AC production and p38 activation. Blockage of p38 MAPK led to suppression of MUC5AC mRNA expression. Notably, mucin production was enhanced in the airway epithelia of mev/+ mice exposed to oxidative stress. Our results clearly indicate that SHP-1 plays an important role in airway mucin production through regulating oxidative stress.
Jang
Min Kyoung
MK
Asan Institute for Life Science, Seoul, Republic of Korea.
Kim
Sae-Hoon
SH
Lee
Ki-Young
KY
Kim
Tae-Bum
TB
Moon
Keun Ae
KA
Park
Chan Sun
CS
Bae
Yun Jeong
YJ
Zhu
Zhou
Z
Moon
Hee-Bom
HB
Cho
You Sook
YS
D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D055271:Mucin 5AC / Q000096:biosynthesis* / Q000235:genetics; D009093:Mucus / Q000378:metabolism; D018384:Oxidative Stress; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
D055271:Mucin 5AC; D006861:Hydrogen Peroxide; D048051:p38 Mitogen-Activated Protein Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6