IKK alpha causes chromatin modification on pro-inflammatory genes by cigarette smoke in mouse lung.
Cigarette smoke (CS) induces abnormal and sustained lung inflammation; however, the molecular mechanism underlying sustained inflammation is not known. It is well known that activation of I kappaB kinase beta (IKK beta) leads to transient translocation of active NF-kappaB (RelA/p65-p50) in the nucleus and transcription of pro-inflammatory genes, whereas the role of IKK alpha in perpetuation of sustained inflammatory response is not known. We hypothesized that CS activates IKK alpha and causes histone acetylation on the promoters of pro-inflammatory genes, leading to sustained transcription of pro-inflammatory mediators in mouse lung in vivo and in human monocyte/macrophage cell line (MonoMac6) in vitro. CS exposure to C57BL/6J mice resulted in activation of IKK alpha, leading to phosphorylation of ser10 and acetylation of lys9 on histone H3 on the promoters of IL-6 and MIP-2 genes in mouse lung. The increased level of IKK alpha was associated with increased acetylation of lys310 RelA/p65 on pro-inflammatory gene promoters. The role of IKK alpha in CS-induced chromatin modification was confirmed by gain and loss of IKK alpha in MonoMac6 cells. Overexpression of IKK alpha was associated with augmentation of CS-induced pro-inflammatory effects, and phosphorylation of ser10 and acetylation of lys9 on histone H3, whereas transfection of IKK alpha dominant-negative mutants reduced CS-induced chromatin modification and pro-inflammatory cytokine release. Moreover, phosphorylation of ser276 and acetylation of lys310 of RelA/p65 was augmented in response to CS extract in MonoMac6 cells transfected with IKK alpha. Taken together, these data suggest that IKK alpha plays a key role in CS-induced pro-inflammatory gene transcription through phospho-acetylation of both RelA/p65 and histone H3.
Yang
Se-Ran
SR
Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Ave., Rochester, NY 14642, USA.
Valvo
Samantha
S
Yao
Hongwei
H
Kode
Aruna
A
Rajendrasozhan
Saravanan
S
Edirisinghe
Indika
I
Caito
Samuel
S
Adenuga
David
D
Henry
Ryan
R
Fromm
George
G
Maggirwar
Sanjay
S
Li
Jian-Dong
JD
Bulger
Michael
M
Rahman
Irfan
I
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D003470:Culture Media / Q000737:chemistry; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D005786:Gene Expression Regulation; D006657:Histones / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology; D011401:Promoter Regions, Genetic; D012907:Smoking / Q000009:adverse effects; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology
D002843:Chromatin; D003470:Culture Media; D006657:Histones; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase