Hypoxia-induced IL-6 production is associated with activation of MAP kinase, HIF-1, and NF-kappaB on HEI-OC1 cells.
In the present study, we investigated the signal transduction pathways of expression of IL-6 in the desferrioxamine (DFX)-stimulated cochlear auditory cell line, HEI-OC1 cells. DFX increased the expression of HIF-1alpha and NF-kappaB in HEI-OC1 cells. DFX significantly increased the production of IL-6 (P<0.05) and expression of IL-6 mRNA but did not affect TNF-alpha production. DFX also induced the activation of mitogen-activated protein kinase (MAPK) including p38, ERK, and JNK on HEI-OC1. Increased IL-6 by DFX was significantly inhibited by p38 inhibitor, SB203580 (about 72% inhibition, P=0.027) but not ERK inhibitor, PD98059 or JNK inhibitor, SP600125. SB203580 inhibited the expression of IL-6 mRNA. Increased IL-6 production was partially inhibited by treatment of iron (HIF-1 inhibitor) or pyrriolidine-dithiocarbamate (PDTC, NF-kappaB inhibitor). DFX also induced IL-6 production and HIF-1alpha expression in the inner ear. We demonstrated the regulatory effects of MAPK, HIF-1alpha, and NF-kappaB on DFX-induced IL-6 production in a HEI-OC1 for the first time. In conclusion, these data indicate that regulation of inflammatory cytokine IL-6 by DFX, through mimicking hypoxic conditions, might explain its beneficial effect in the treatment of hypoxia-induced inner ear diseases.
Jeong
Hyun-Ja
HJ
College of Oriental Medicine, Kyung Hee University, 1 Hoegi-Dong, Dongdaemun-Gu, Seoul 130-701, Republic of Korea.
Hong
Seung-Heon
SH
Park
Rae-Kil
RK
Shin
Taekyun
T
An
Nyeon-Hyoung
NH
Kim
Hyung-Min
HM
D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia / Q000276:immunology / Q000502:physiology*; D002460:Cell Line; D003051:Cochlea / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D003676:Deferoxamine / Q000494:pharmacology; D007758:Ear, Inner / Q000187:drug effects / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
D018076:DNA, Complementary; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; C015482:protein kinase modulator; D003676:Deferoxamine