IL-6 rescues the hyporesponsiveness of c-Rel deficient B cells independent of Bcl-xL, Mcl-1, and Bcl-2.
The hematopoietically restricted member of the NF-kappaB/Rel family, c-Rel, is essential for B cell survival and proliferation. Here we demonstrate that the production of the interleukins 6, 10, and 15 (IL-6, IL-10, and IL-15) are diminished in c-Rel(-/-) B lymphocytes. In a manner similar to that seen in IL-6(-/-) B cells, resultant STAT activation is reduced in c-Rel(-/-) B cells following B cell receptor (BCR) ligation. Addition of either exogenous IL-6 or IL-10, but not IL-15, partially restores proliferation, and this occurs through enhanced cell survival rather than promoting cell cycle progression. This increase in viability occurs independently of Bcl-xL and Mcl-1 expression though, two survival genes reported to be downstream of IL-6 signaling. Nonetheless, transgenically expressed Bcl-xL, a direct c-Rel target gene in B cells, corrects not only the survival defect of c-Rel deficiency, but also partially ameliorates hypoproliferation. Together IL-6 and Bcl-xL are additive but incomplete in the restoration of proliferation. Known deficits in the induction of several key cell cycle components in c-Rel(-/-)B cells are not corrected upon treatment with exogenous cytokine. Together, these data demonstrate that IL-6 enhances B cell responses by employing multiple survival factors.
Tumang
Joseph R
JR
Department of Medicine, Division of Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Hsia
Constance Y
CY
Tian
Wenzhi
W
Bromberg
Jacqueline F
JF
Liou
Hsiou-Chi
HC
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D015850:Interleukin-6; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D051020:bcl-X Protein