The Journal of Immunology, Vol 158, Issue 11 5211-5218, Copyright © 1997 by American Association of Immunologists

ARTICLES

Multifocal defects in immune responses in RelB-deficient mice

F Weih, G Warr, H Yang and R Bravo
Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.

Mice with a targeted disruption of the Rel/nuclear factor-kappaB family member RelB develop a complex inflammatory phenotype, myeloid hyperplasia, and splenomegaly due to extramedullary hemopoiesis. In this work, we report that RelB-deficient mice, in addition to the pathologic changes, were highly susceptible to infection by the facultative intracellular bacterium Listeria monocytogenes. RelB binds transcriptionally active kappaB motifs in the TNF-alpha promoter in normal cells, and in vitro studies with macrophages isolated from RelB- deficient animals revealed impaired production of TNF-alpha in response to LPS and IFN-gamma. RelB-deficient mice also were unable to mount a protective immune response against lymphocytic choriomeningitis virus. These results indicate a defective T cell-macrophage interaction and cytotoxic T cell response, respectively, in mice lacking RelB. Analysis of resting and specific Ab production demonstrated that while RelB is not required for the secretion of Ig isotypes that result from heavy chain class switching, it is necessary for normal production of Ag- specific IgG in response to T cell-dependent and -independent stimuli. Thus, RelB is not only essential for a normal hemopoietic system in the unchallenged animal, but also involved in various specific and nonspecific immune responses.

This article has been cited by other articles:

				P. Lupo, Y. C. Chang, B. L. Kelsall, J. M. Farber, D. Pietrella, A. Vecchiarelli, F. Leon, and K. J. Kwon-Chung The Presence of Capsule in Cryptococcus neoformans Influences the Gene Expression Profile in Dendritic Cells during Interaction with the Fungus Infect. Immun., April 1, 2008; 76(4): 1581 - 1589. [Abstract] [Full Text] [PDF]

				Z. U. A. Mollah, S. Pai, C. Moore, B. J. O'Sullivan, M. J. Harrison, J. Peng, K. Phillips, J. B. Prins, J. Cardinal, and R. Thomas Abnormal NF-{kappa}B Function Characterizes Human Type 1 Diabetes Dendritic Cells and Monocytes J. Immunol., March 1, 2008; 180(5): 3166 - 3175. [Abstract] [Full Text] [PDF]

				A. Schwegmann, R. Guler, A. J. Cutler, B. Arendse, W. G. C. Horsnell, A. Flemming, A. H. Kottmann, G. Ryan, W. Hide, M. Leitges, et al. Protein kinase C {delta} is essential for optimal macrophage-mediated phagosomal containment of Listeria monocytogenes PNAS, October 9, 2007; 104(41): 16251 - 16256. [Abstract] [Full Text] [PDF]

				N. D. Mineva, T. L. Rothstein, J. A. Meyers, A. Lerner, and G. E. Sonenshein CD40 Ligand-mediated Activation of the de Novo RelB NF-{kappa}B Synthesis Pathway in Transformed B Cells Promotes Rescue from Apoptosis J. Biol. Chem., June 15, 2007; 282(24): 17475 - 17485. [Abstract] [Full Text] [PDF]

				C. Martucci, S. Franchi, D. Lattuada, A. E. Panerai, and P. Sacerdote Differential involvement of RelB in morphine-induced modulation of chemotaxis, NO, and cytokine production in murine macrophages and lymphocytes J. Leukoc. Biol., January 1, 2007; 81(1): 344 - 354. [Abstract] [Full Text] [PDF]

				K. A. Shirey, J.-Y. Jung, and J. M. Carlin Up-Regulation of Gamma Interferon Receptor Expression Due to Chlamydia-Toll-Like Receptor Interaction Does Not Enhance Signal Transducer and Activator of Transcription 1 Signaling Infect. Immun., December 1, 2006; 74(12): 6877 - 6884. [Abstract] [Full Text] [PDF]

				B. K. Yoza, J. Y.-Q. Hu, S. L. Cousart, L. M. Forrest, and C. E. McCall Induction of RelB Participates in Endotoxin Tolerance J. Immunol., September 15, 2006; 177(6): 4080 - 4085. [Abstract] [Full Text] [PDF]

				R. P. Deering and J. S. Orange Development of a Clinical Assay To Evaluate Toll-Like Receptor Function Clin. Vaccine Immunol., January 1, 2006; 13(1): 68 - 76. [Abstract] [Full Text] [PDF]

				E. Jacque, T. Tchenio, G. Piton, P.-H. Romeo, and V. Baud RelA repression of RelB activity induces selective gene activation downstream of TNF receptors PNAS, October 11, 2005; 102(41): 14635 - 14640. [Abstract] [Full Text] [PDF]

				P. J. Cejas, L. M. Carlson, D. Kolonias, J. Zhang, I. Lindner, D. D. Billadeau, L. H. Boise, and K. P. Lee Regulation of RelB Expression during the Initiation of Dendritic Cell Differentiation Mol. Cell. Biol., September 1, 2005; 25(17): 7900 - 7916. [Abstract] [Full Text] [PDF]

				E. Hollenbach, M. Vieth, A. Roessner, M. Neumann, P. Malfertheiner, and M. Naumann Inhibition of RICK/Nuclear Factor-{kappa}B and p38 Signaling Attenuates the Inflammatory Response in a Murine Model of Crohn Disease J. Biol. Chem., April 15, 2005; 280(15): 14981 - 14988. [Abstract] [Full Text] [PDF]

				T. Shiina, A. Konno, T. Oonuma, H. Kitamura, K. Imaoka, N. Takeda, K. Todokoro, and M. Morimatsu Targeted Disruption of MAIL, a Nuclear I{kappa}B Protein, Leads to Severe Atopic Dermatitis-like Disease J. Biol. Chem., December 31, 2004; 279(53): 55493 - 55498. [Abstract] [Full Text] [PDF]

				S. I. Samson, S. Memet, C. A. J. Vosshenrich, F. Colucci, O. Richard, D. Ndiaye, A. Israel, and J. P. Di Santo Combined deficiency in I{kappa}B{alpha} and I{kappa}B{epsilon} reveals a critical window of NF-{kappa}B activity in natural killer cell differentiation Blood, June 15, 2004; 103(12): 4573 - 4580. [Abstract] [Full Text] [PDF]

				H. J. Maier, R. Marienfeld, T. Wirth, and B. Baumann Critical Role of RelB Serine 368 for Dimerization and p100 Stabilization J. Biol. Chem., October 3, 2003; 278(40): 39242 - 39250. [Abstract] [Full Text] [PDF]

				E. Derudder, E. Dejardin, L. L. Pritchard, D. R. Green, M. Korner, and V. Baud RelB/p50 Dimers Are Differentially Regulated by Tumor Necrosis Factor-{alpha} and Lymphotoxin-{beta} Receptor Activation: CRITICAL ROLES FOR p100 J. Biol. Chem., June 20, 2003; 278(26): 23278 - 23284. [Abstract] [Full Text] [PDF]

				R. Marienfeld, M. J. May, I. Berberich, E. Serfling, S. Ghosh, and M. Neumann RelB Forms Transcriptionally Inactive Complexes with RelA/p65 J. Biol. Chem., May 23, 2003; 278(22): 19852 - 19860. [Abstract] [Full Text] [PDF]

				C. M. Tato, A. Villarino, J. H. Caamano, M. Boothby, and C. A. Hunter Inhibition of NF-{kappa}B Activity in T and NK Cells Results in Defective Effector Cell Expansion and Production of IFN-{gamma} Required for Resistance to Toxoplasma gondii J. Immunol., March 15, 2003; 170(6): 3139 - 3146. [Abstract] [Full Text] [PDF]

				D. Artis, K. Speirs, K. Joyce, M. Goldschmidt, J. Caamano, C. A. Hunter, and P. Scott NF-{kappa}B1 Is Required for Optimal CD4+ Th1 Cell Development and Resistance to Leishmania major J. Immunol., February 15, 2003; 170(4): 1995 - 2003. [Abstract] [Full Text] [PDF]

				D. Bhattacharya, D. U. Lee, and W. C. Sha Regulation of Ig class switch recombination by NF-{kappa}B: retroviral expression of RelB in activated B cells inhibits switching to IgG1, but not to IgE Int. Immunol., September 1, 2002; 14(9): 983 - 991. [Abstract] [Full Text] [PDF]

				J. Caamano and C. A. Hunter NF-{kappa}B Family of Transcription Factors: Central Regulators of Innate and Adaptive Immune Functions Clin. Microbiol. Rev., July 1, 2002; 15(3): 414 - 429. [Abstract] [Full Text] [PDF]

				C. M. Tato and C. A. Hunter Host-Pathogen Interactions: Subversion and Utilization of the NF-{kappa}B Pathway during Infection Infect. Immun., July 1, 2002; 70(7): 3311 - 3317. [Full Text] [PDF]

				B. J. O'Sullivan and R. Thomas CD40 Ligation Conditions Dendritic Cell Antigen-Presenting Function Through Sustained Activation of NF-{kappa}B J. Immunol., June 1, 2002; 168(11): 5491 - 5498. [Abstract] [Full Text] [PDF]

				K. Speirs, J. Caamano, M. H. Goldschmidt, C. A. Hunter, and P. Scott NF-{kappa}B2 Is Required for Optimal CD40-Induced IL-12 Production but Dispensable for Th1 Cell Differentiation J. Immunol., May 1, 2002; 168(9): 4406 - 4413. [Abstract] [Full Text] [PDF]

				H. Ren, A. Schmalstieg, N. S. C. van Oers, and R. B. Gaynor I-{kappa}B Kinases {alpha} and {beta} Have Distinct Roles in Regulating Murine T Cell Function J. Immunol., April 15, 2002; 168(8): 3721 - 3731. [Abstract] [Full Text] [PDF]

				M. D. Saemann, O. Parolini, G. A. Bohmig, P. Kelemen, P.-M. Krieger, J. Neumuller, K. Knarr, W. Kammlander, W. H. Horl, C. Diakos, et al. Bacterial metabolite interference with maturation of human monocyte-derived dendritic cells J. Leukoc. Biol., February 1, 2002; 71(2): 238 - 246. [Abstract] [Full Text] [PDF]

				H. Ren, A. Schmalstieg, D. Yuan, and R. B. Gaynor I-{kappa}B Kinase {beta} Is Critical for B Cell Proliferation and Antibody Response J. Immunol., January 15, 2002; 168(2): 577 - 587. [Abstract] [Full Text] [PDF]

				C. M. Weyand, P. J. Kurtin, and J. J. Goronzy Ectopic Lymphoid Organogenesis : A Fast Track for Autoimmunity Am. J. Pathol., September 1, 2001; 159(3): 787 - 793. [Full Text] [PDF]

				D. S. Weih, Z. B. Yilmaz, and F. Weih Essential Role of RelB in Germinal Center and Marginal Zone Formation and Proper Expression of Homing Chemokines J. Immunol., August 15, 2001; 167(4): 1909 - 1919. [Abstract] [Full Text] [PDF]

				J. Caamano, C. Tato, G. Cai, E. N. Villegas, K. Speirs, L. Craig, J. Alexander, and C. A. Hunter Identification of a Role for NF-{kappa}B2 in the Regulation of Apoptosis and in Maintenance of T Cell-Mediated Immunity to Toxoplasma gondii J. Immunol., November 15, 2000; 165(10): 5720 - 5728. [Abstract] [Full Text] [PDF]

				B. J. O'Sullivan, K. P. A. MacDonald, A. R. Pettit, and R. Thomas RelB nuclear translocation regulates B cell MHC molecule, CD40 expression, and antigen-presenting cell function PNAS, October 10, 2000; 97(21): 11421 - 11426. [Abstract] [Full Text] [PDF]

				L. A. Lyakh, G. K. Koski, W. Telford, R. E. Gress, P. A. Cohen, and N. R. Rice Bacterial Lipopolysaccharide, TNF-{alpha}, and Calcium Ionophore Under Serum-Free Conditions Promote Rapid Dendritic Cell-Like Differentiation in CD14+ Monocytes Through Distinct Pathways That Activate NF-{kappa}B J. Immunol., October 1, 2000; 165(7): 3647 - 3655. [Abstract] [Full Text] [PDF]

				R. K.G. Do, E. Hatada, H. Lee, M. R. Tourigny, D. Hilbert, and S. Chen-Kiang Attenuation of Apoptosis Underlies B Lymphocyte Stimulator Enhancement of Humoral Immune Response J. Exp. Med., September 25, 2000; 192(7): 953 - 964. [Abstract] [Full Text] [PDF]

				K. M. Ardeshna, A. R. Pizzey, S. Devereux, and A. Khwaja The PI3 kinase, p38 SAP kinase, and NF-kappa B signal transduction pathways are involved in the survival and maturation of lipopolysaccharide-stimulated human monocyte-derived dendritic cells Blood, August 1, 2000; 96(3): 1039 - 1046. [Abstract] [Full Text] [PDF]

				S. Memet, D. Laouini, J.-C. Epinat, S. T. Whiteside, B. Goudeau, D. Philpott, S. Kayal, P. J. Sansonetti, P. Berche, J. Kanellopoulos, et al. I{kappa}B{epsilon}-Deficient Mice: Reduction of One T Cell Precursor Subspecies and Enhanced Ig Isotype Switching and Cytokine Synthesis J. Immunol., December 1, 1999; 163(11): 5994 - 6005. [Abstract] [Full Text] [PDF]

				Y. Xia, S. Chen, Y. Wang, N. Mackman, G. Ku, D. Lo, and L. Feng RelB Modulation of Ikappa Balpha Stability as a Mechanism of Transcription Suppression of Interleukin-1alpha (IL-1alpha ), IL-1beta , and Tumor Necrosis Factor Alpha in Fibroblasts Mol. Cell. Biol., November 1, 1999; 19(11): 7688 - 7696. [Abstract] [Full Text] [PDF]

				J. Caamano, J. Alexander, L. Craig, R. Bravo, and C. A. Hunter The NF-{kappa}B Family Member RelB Is Required for Innate and Adaptive Immunity to Toxoplasma gondii J. Immunol., October 15, 1999; 163(8): 4453 - 4461. [Abstract] [Full Text] [PDF]

				L. Harling-McNabb, G. Deliyannis, D. C. Jackson, S. Gerondakis, G. Grigoriadis, and L. E. Brown Mice lacking the transcription factor subunit Rel can clear an influenza infection and have functional anti-viral cytotoxic T cells but do not develop an optimal antibody response Int. Immunol., September 1, 1999; 11(9): 1431 - 1439. [Abstract] [Full Text] [PDF]

				C. Mohan, Y. Yu, L. Morel, P. Yang, and E. K. Wakeland Genetic Dissection of Sle Pathogenesis: Sle3 on Murine Chromosome 7 Impacts T Cell Activation, Differentiation, and Cell Death J. Immunol., June 1, 1999; 162(11): 6492 - 6502. [Abstract] [Full Text] [PDF]

				H.-C. Liou, Z. Jin, J. Tumang, S. Andjelic, K. A. Smith, and M.-L. Liou c-Rel is crucial for lymphocyte proliferation but dispensable for T cell effector function Int. Immunol., March 1, 1999; 11(3): 361 - 371. [Abstract] [Full Text] [PDF]

				F. Chen, V. Castranova, X. Shi, and L. M. Demers New Insights into the Role of Nuclear Factor-{kappa}B, a Ubiquitous Transcription Factor in the Initiation of Diseases Clin. Chem., January 1, 1999; 45(1): 7 - 17. [Abstract] [Full Text] [PDF]

				S.-C. Lin, H. H. Wortis, and J. Stavnezer The Ability of CD40L, but Not Lipopolysaccharide, To Initiate Immunoglobulin Switching to Immunoglobulin G1 Is Explained by Differential Induction of NF-kappa B/Rel Proteins Mol. Cell. Biol., September 1, 1998; 18(9): 5523 - 5532. [Abstract] [Full Text]

				J. H. Caamano, C. A. Rizzo, S. K. Durham, D. S. Barton, C. Raventos-Suarez, C. M. Snapper, and R. Bravo Nuclear Factor (NF)-kappa B2 (p100/p52) Is Required for Normal Splenic Microarchitecture and B Cell-mediated Immune Responses J. Exp. Med., January 19, 1998; 187(2): 185 - 196. [Abstract] [Full Text] [PDF]