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RelB Is Differentially Regulated by IB Kinase- in B Cells and Mouse Lung by Cigarette Smoke

¹ Department of Environmental Medicine, Lung Biology and Disease Program, and ² Departments of Pediatrics, ³ Microbiology and Immunology, and ⁴ Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York

Correspondence and requests for reprints should be addressed to Irfan Rahman, Ph.D., Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Ave., Rochester, NY 14642. E-mail: irfan_rahman{at}urmc.rochester.edu

The activation of transcription factor NF-B is controlled by two main pathways: the classical canonical (RelA/p65-p50)- and the alternative noncanonical (RelB/p52)–NF-B 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-B–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 IB-kinase- and double mutants of NF-B–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 IB-kinase-–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.

Key Words: chronic obstructive pulmonary disease • cigarette smoke • NF-B • RelB • B cells

CLINICAL RELEVANCE RelB is rapidly degraded in B cells, but not in macrophages and mouse lungs, in response to cigarette smoke exposure. RelB may be a potential target in controlling inflammation in lymphoid immune cells of patients with chronic obstructive pulmonary disease.