Submitted on June 5, 2008
Revised on August 6, 2008
RelB is differentially regulated by I
B-Kinase
(IKK) in B Cells and Mouse Lung by Cigarette Smoke
Se-Ran Yang1, Hongwei Yao1, Saravanan Rajendrasozhan1, Sangwoon Chung1, Indika Edirisinghe1, Samantha Valvo1, George Fromm2, Michael J McCabe Jr1, Patricia J Sime1, Richard P Phipps3, Jian-Dong Li4, Michael Bulger2, and Irfan Rahman1*
1 Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York, USA,
2 Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA,
3 Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York, USA; Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA,
4 Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
* To whom correspondence should be addressed. E-mail: Irfan_Rahman{at}urmc.rochester.edu.
The transcription factor NF-
B activation is controlled by two main pathways: the classical canonical (RelA/p65-p50)- and the alternative non-canonical (RelB/p52)-NF-B pathways. RelB has been shown to play a protective role in RelA/p65-mediated pro-inflammatory cytokine release in immune-inflammatory lymphoid cells. Increased infiltration of macrophages and lymphoid cells occurs in lungs of patients with COPD 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 pro-inflammatory cytokines in response to cigarette smoke (CS). CS exposure increased the levels of RelB and NF-B-inducing kinase (NIK), associated with recruitment of RelB on promoters of the IL-6 and MIP-2 genes in mouse lung. Treatment of macrophage cell line (MonoMac6) with cigarette smoke extract (CSE) 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 IB-kinase (IKK
) and double mutants of NIK partially attenuated the CSE-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 IKK, and rapid degradation of RelB signals for RelA/p65 activation and loss of its protective ability to suppress the pro-inflammatory cytokine release in lymphoid B cells.
