Manganese-mediated up-regulation of HIF-1alpha protein in Hep2 human laryngeal epithelial cells via activation of the family of MAPKs.
High exposure of manganese is believed to be a risk factor for respiratory diseases. Evidence suggests that overexpression of HIF-1alpha transcription factor is linked to pulmonary inflammation and vascular change. In this study, we investigated the effect of manganese-chloride (manganese) on expression and activity of HIF-1alpha in various human airway cells, including Hep2 (laryngeal), H292 (bronchial), and A549 (lung). Profoundly, while manganese treatment led to low or little effect on induction of HIF-1alpha protein in H292 or A549 cells, it strongly induced HIF-1alpha protein expression in Hep2 cells. Mn treatment, however, did not induce HIF-1alpha mRNA expression in Hep2 cells. Luciferase experiments further demonstrated that manganese treatment increased the HRE-driven luciferase activity, suggesting that the induced HIF-1 is functional. Interestingly, manganese treatment also caused activation of p38 MAPK, JNK-1/2, ERK-1/2, and ATF-2, but not of PKB or NF-kappaB in Hep2 cells. Importantly, the manganese-mediated expression and activity of HIF-1alpha protein were largely blocked by treatment with the inhibitor of p38 MAPK (SB203580), JNK-1/2 (SP600125), or ERK-1/2 (PD98059), suggesting roles of these MAPKs in the manganese-induced HIF-1alpha protein expression and activity. Moreover, treatment with SP600125 or SB203580, but not PD98059, had partial inhibitory effects on the stability of HIF-1alpha protein induced by manganese, suggesting that p38 MAPK and JNK-1/2 also contribute to the Mn-mediated HIF-1alpha protein stability. These results suggest that manganese is able to up-regulate HIF-1alpha at the protein level in Hep2 cells and the up-regulation is largely dependent of activities of the family of MAPKs.
Department of Medical Genetic Engineering, Keimyung University School of Medicine, 194 Dongsan-dong, Jung-gu, Daegu 700-712, South Korea.
Hee-Jung
HJ
Shin
Mi-Sun
MS
Choi
Nam-Hee
NH
Ryoo
Ki-Young
KY
Nam
Gy-Young
GY
Park
Jae-Hoon
JH
Bae
Seong-il
SI
Suh
Won-Ki
WK
Baek
Jong-Wook
JW
Park
Byeong-Churl
BC
Jang
D002460:Cell Line; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007830:Larynx / Q000166:cytology; D008345:Manganese / Q000633:toxicity*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D004785:Environmental Pollutants; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008345:Manganese; D020928:Mitogen-Activated Protein Kinases