title: RelB is differentially regulated by IkappaB Kinase-alpha in B cells and mouse lung by cigarette smoke.
abstract: The activation of transcription factor NF-kappaB is controlled by two main pathways: the classical canonical (RelA/p65-p50)- and the alternative noncanonical (RelB/p52)-NF-kappaB pathways. RelB has been shown to play a protective role in RelA/p65-mediated proinflammatory cytokine release in immune-inflammatory lymphoid cells. Increased infiltration of macrophages and lymphoid cells occurs in lungs of patients with chronic obstructive pulmonary disease, leading to abnormal inflammation. We hypothesized that RelB, and its signaling pathway, is differentially regulated in macrophages and B cells and in lung cells, leading to differential regulation of proinflammatory cytokines in response to cigarette smoke (CS). CS exposure increased the levels of RelB and NF-kappaB-inducing kinase associated with recruitment of RelB on promoters of the IL-6 and macrophage inflammatory protein-2 genes in mouse lung. Treatment of macrophage cell line, MonoMac6, with CS extract showed activation of RelB. In contrast, RelB was degraded by a proteasome-dependent mechanism in B lymphocytes (human Ramos, mouse WEHI-231, and primary mouse spleen B cells), suggesting that RelB is differentially regulated in lung inflammatory and lymphoid cells in response to CS exposure. Transient transfection of dominant negative IkappaB-kinase-alpha and double mutants of NF-kappaB-inducing kinase partially attenuated the CS extract-mediated loss of RelB in B cells and normalized the increased RelB level in macrophages. Taken together, these data suggest that RelB is differentially regulated in response to CS exposure in macrophages, B cells, and in lung cells by IkappaB-kinase-alpha-dependent mechanism. Rapid degradation of RelB signals for RelA/p65 activation and loss of its protective ability to suppress the proinflammatory cytokine release in lymphoid B cells.
authors.affiliation: Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Ave., Rochester, NY 14642, USA.
authors.forename: Se-Ran
authors.initials: SR
authors.lastname: Yang
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.forename: Saravanan
authors.initials: S
authors.lastname: Rajendrasozhan
authors.forename: Sangwoon
authors.initials: S
authors.lastname: Chung
authors.forename: Indika
authors.initials: I
authors.lastname: Edirisinghe
authors.forename: Samantha
authors.initials: S
authors.lastname: Valvo
authors.forename: George
authors.initials: G
authors.lastname: Fromm
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCabe
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Bulger
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D053308:Lymphotoxin-beta / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism; D011014:Pneumonia / Q000209:etiology / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000378:metabolism; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*; D051996:Transcription Factor RelA / Q000378:metabolism; D051841:Transcription Factor RelB / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; C505887:Ltb protein, mouse; D053308:Lymphotoxin-beta; C497593:RELB protein, human; C498144:Rela protein, mouse; C497594:Relb protein, mouse; D051996:Transcription Factor RelA; D023201:CD40 Ligand; D051841:Transcription Factor RelB; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase