BCL-3 and NF-κB p50 Attenuate Lipopolysaccharide-induced Inflammatory Responses in Macrophages
Lipopolysaccharide (LPS) induces expression of tumor necrosis factor α (TNFα) and other pro-inflammatory cytokines in macrophages. Following its induction, TNFα gene transcription is rapidly attenuated, in part due to the accumulation of NF-κB p50 homodimers that bind to three κB sites in the TNFα promoter. Here we have investigated the inhibitory role of BCL-3, an IκB-like protein that interacts exclusively with p50 and p52 homodimers. BCL-3 was induced by LPS with delayed kinetics and was associated with p50 in the nucleus. Forced expression of BCL-3 suppressed LPS-induced transcription from the TNFα promoter and inhibited two artificial promoters composed of TNFακB sites that preferentially bind p50 dimers. BCL-3-mediated repression was reversed by trichostatin A and was enhanced by overexpression of HDAC-1, indicating that transcriptional attenuation involves recruitment of histone deacetylase. Analysis of macrophages from p50 and BCL-3 knock-out mice revealed that both transcription factors negatively regulate TNFα expression and that BCL-3 inhibits IL-1α and IL-1β. In contrast, induction of the anti-inflammatory cytokine IL-10 was reduced in BCL-3 null macrophages. BCL-3 was not required for the production of p50 homodimers but BCL-3 expression was severely diminished in p50-deficient cells. Together, these findings indicate that p50 and BCL-3 function as anti-inflammatory regulators in macrophages by attenuating transcription of pro-inflammatory cytokines and activating IL-10 expression. Lipopolysaccharide (LPS) induces expression of tumor necrosis factor α (TNFα) and other pro-inflammatory cytokines in macrophages. Following its induction, TNFα gene transcription is rapidly attenuated, in part due to the accumulation of NF-κB p50 homodimers that bind to three κB sites in the TNFα promoter. Here we have investigated the inhibitory role of BCL-3, an IκB-like protein that interacts exclusively with p50 and p52 homodimers. BCL-3 was induced by LPS with delayed kinetics and was associated with p50 in the nucleus. Forced expression of BCL-3 suppressed LPS-induced transcription from the TNFα promoter and inhibited two artificial promoters composed of TNFακB sites that preferentially bind p50 dimers. BCL-3-mediated repression was reversed by trichostatin A and was enhanced by overexpression of HDAC-1, indicating that transcriptional attenuation involves recruitment of histone deacetylase. Analysis of macrophages from p50 and BCL-3 knock-out mice revealed that both transcription factors negatively regulate TNFα expression and that BCL-3 inhibits IL-1α and IL-1β. In contrast, induction of the anti-inflammatory cytokine IL-10 was reduced in BCL-3 null macrophages. BCL-3 was not required for the production of p50 homodimers but BCL-3 expression was severely diminished in p50-deficient cells. Together, these findings indicate that p50 and BCL-3 function as anti-inflammatory regulators in macrophages by attenuating transcription of pro-inflammatory cytokines and activating IL-10 expression. Macrophages are a primary source of the pro-inflammatory cytokine TNFα, 1The abbreviations used are: TNFα, tumor necrosis factor α; LPS, lipopolysaccharide; IL, interleukin; wt, wild-type; TIF, TNFα inhibitory factor; GM-CSF, granulocyte macrophage colony-stimulating factor; TSA, trichostatin A; HDAC, histone deacetylase; MΦ, macrophage; EMSA, electrophoretic mobility shift assay; RPA, ribonuclease protection assay; FACS, fluorescence-activated cell sorting; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; CMV, cytomegalovirus; PBS, phosphate-buffered saline; M-CSF, macrophage CSF. which is expressed in response to viral or bacterial infection and other inflammatory stimuli. TNFα evokes numerous responses in immune cells and surrounding tissues, such as expression of ICAM-1 (intercellular adhesion molecule-1) on the surface of epithelial cells to promote adhesion and infiltration of neutrophils and monocytes (1Voraberger G. Schafer R. Stratowa C. J. Immunol. 1991; 147: 2777-2786Crossref PubMed Google Scholar, 2Ledebur H.C. Parks T.P. J. Biol. Chem. 1995; 270: 933-943Abstract Full Text Full Text PDF PubMed Scopus (519) Google Scholar). TNFα also induces the secretion of proteinases that degrade intercellular matrix proteins and allow macrophages to penetrate tissue to the site of injury or infection (3Tracey K.J. Cerami A. Annu. Rev. Med. 1994; 45: 491-503Crossref PubMed Scopus (962) Google Scholar) and stimulates macrophages to produce other pro-inflammatory cytokines that modulate immune functions. Although TNFα plays a beneficial role by rapidly activating immune cells and eliciting other cellular responses that protect the host from infection and injury, prolonged or elevated expression of TNFα is associated with a number of pathological conditions, including chronic inflammation (4Cerami A. Blood Purif. 1993; 11: 108-117Crossref PubMed Scopus (22) Google Scholar), septic shock (5Tracey K.J. Circ. Shock. 1991; 35: 123-128PubMed Google Scholar), cachexia (3Tracey K.J. Cerami A. Annu. Rev. Med. 1994; 45: 491-503Crossref PubMed Scopus (962) Google Scholar), and autoimmune diseases such as rheumatoid arthritis (6Schattner A. Clin. Immunol. Immunopathol. 1994; 70: 177-189Crossref PubMed Scopus (76) Google Scholar, 7Feldmann M. Brennan F.M. Elliott M.J. Williams R.O. Maini R.N. Ann. N. Y. Acad. Sci. 1995; 766: 272-278Crossref PubMed Scopus (76) Google Scholar). The potentially deleterious effects of TNFα require stringent control over its expression. Previously we described a mechanism that attenuates LPS-induced transcription of the TNFα gene in macrophages (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar). LPS-stimulated macrophages were found to secrete a soluble activity called TNFα inhibitory factor (TIF) that suppressed the induction of TNFα mRNA by endotoxin. In addition to inhibiting TNFα expression, TIF caused the selective nuclear accumulation of NF-κB p50 homodimers. NF-κB p50, a member of the Rel family of transcription factors, lacks transcriptional activation domains and is capable of inhibiting transcription of target genes (9Ghosh S. May M.J. Kopp E.B. Annu. Rev. Immunol. 1998; 16: 225-260Crossref PubMed Scopus (4657) Google Scholar). p50 dimers accumulate with delayed kinetics in macrophages following LPS stimulation and preferentially bind to three κB elements in the murine TNFα promoter (κB1, κB2a, and κB3). Binding of p50 dimers appears to play a key role in attenuating TNFα gene transcription (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar, 10Bohuslav J. Kravchenko V.V. Parry G.C. Erlich J.H. Gerondakis S. Mackman N. Ulevitch R.J. J. Clin. Invest. 1998; 102: 1645-1652Crossref PubMed Scopus (243) Google Scholar, 11Kastenbauer S. Ziegler-Heitbrock H.W. Infect. Immun. 1999; 67: 1553-1559Crossref PubMed Google Scholar). This notion is further supported by the fact that a genetic polymorphism that disrupts binding of p50 dimers to the κB1 site in the human TNFα gene causes increased transcription from this promoter (12Udalova I.A. Richardson A. Denys A. Smith C. Ackerman H. Foxwell B. Kwiatkowski D. Mol. Cell. Biol. 2000; 20: 9113-9119Crossref PubMed Scopus (212) Google Scholar). Although these findings implicate p50 as an inhibitory factor, the mechanism by which p50 represses TNFα gene transcription has not been fully elucidated. In particular, it is unclear whether other transcription factors or accessory proteins are required for p50-mediated repression of the TNFα gene. In the present study we investigated the role of BCL-3 in attenuating TNFα gene transcription. BCL-3 is a predominantly nuclear member of the IκB family of NF-κB inhibitors whose defining structural feature is the ankyrin repeat motif, which mediates interactions with NF-κB dimers (9Ghosh S. May M.J. Kopp E.B. Annu. Rev. Immunol. 1998; 16: 225-260Crossref PubMed Scopus (4657) Google Scholar). BCL-3 associates with p50 and p52 homodimers but not with other NF-κB dimers (13Fujita T. H.C. D. 1993; PubMed Scopus Google Scholar, T. C. H.C. D. Mol. Cell. Biol. 1993; PubMed Google Scholar). In to the which are in response to BCL-3 not BCL-3 is expressed in in it is induced by BCL-3 are increased by in cells H. G. Cell. Full Text PDF PubMed Scopus Google Scholar, T. D. 1991; Google Scholar), by in cells A. A. Mol. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar), by and in cells 1998; PubMed Google Scholar), and by in cells and cells M. J. 1999; PubMed Google Scholar). In the cells also binding of p50 homodimers and inhibits transcription from a gene. The role of BCL-3 in NF-κB activity has been In BCL-3 (13Fujita T. H.C. D. 1993; PubMed Scopus Google Scholar, 1998; PubMed Google Scholar, G. S. T. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar) or negatively M. J. 1999; PubMed Google Scholar, G. PubMed Scopus Google Scholar) regulate transcription of genes NF-κB has been that BCL-3 transcription by with p50 or p52 dimers on a to the NF-κB (13Fujita T. H.C. D. 1993; PubMed Scopus Google Scholar, G. S. T. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). BCL-3 was also to transcription by the binding of p50 dimers to J.H. R. Mol. Cell. Biol. 16: PubMed Scopus Google Scholar) or by the of p50 homodimers and to the N. T. T. T. J. 16: PubMed Scopus Google Scholar). BCL-3 including production of and increased to bacterial G. T. S. A. T. A. M. A. Full Text Full Text PDF PubMed Scopus Google Scholar, A. 11: PubMed Scopus Google Scholar). with in p50 knock-out H.C. D. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar), and mice enhanced A. 11: PubMed Scopus Google Scholar). The genetic a p50 and BCL-3 in and the of these proteins in immune that BCL-3 play a role in TNFα gene to the of nuclear p50 homodimers or to inhibitory that BCL-3 is induced in macrophages by LPS with delayed kinetics and attenuates LPS-induced TNFα gene transcription. Analysis of and macrophages that both proteins negatively regulate expression of TNFα and other pro-inflammatory BCL-3 also expression of the anti-inflammatory p50 and BCL-3 function to the pro-inflammatory response of macrophages. and macrophages were in Dulbecco's modified Eagle's with fetal bovine which produce the were in with LPS and trichostatin A were from and and artificial NF-κB of NF-κB sites have been described (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar). for p50 and and were described (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar). expression for BCL-3 from T. was from the human BCL-3 gene The BCL-3 was the control of the promoter in the expression The was by C. A. p50 and have been described A. Cell. Full Text PDF PubMed Scopus Google Scholar, J. 1993; PubMed Scopus Google Scholar). A BCL-3 by N. was a to the of the human BCL-3 protein the was to of the to The murine BCL-3 is in this for the the and the with and and were used for of macrophage cell surface human was from Macrophages and macrophages and macrophage cell were from mice p50 H.C. D. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar) or BCL-3 G. T. S. A. T. A. M. A. Full Text Full Text PDF PubMed Scopus Google Scholar) and cells were from and and in phosphate-buffered The cells were by an and for and cells were of was and the cells were primary the cells were in with and for The cells were and cells The primary cells were in DMEM, for to macrophages. macrophage cell cells were in cell source of the PubMed Scopus Google Scholar) with of and of the was and the cells were in DMEM, for was and the cells were further in DMEM, to cell of cell surface was as cells in of phosphate-buffered with bovine were for on with of to the present on the cell The cells were two with PBS, bovine and were in of PBS, bovine were a cells as and with of or for two the cells were with of and by and were by a cell as described M. Williams Dillner A. Schwartz R.C. Johnson P.F. 1998; PubMed Google Scholar). were in and cells were in a and by nuclear or cell were with Scopus Google Scholar), to for and on were to or and with for p50, or were the were as described (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar) nuclear from and macrophages and an to the NF-κB binding site (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar). macrophages were with of of of of a as described (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar). cells were with to LPS the cells were with LPS and cell over a The were for activity the enhanced or the expression was to protein or were to for immune of in of was with of for The were with and in and the were by and for The were with of and for with The was with of with of PBS, with and with of The were in to or were with nuclear for The were and with C. proteins were by with The proteins were with and in of with and on were to and with was from cells and of was used for protection were the and protection were the protection as by the were on the to cytokine were the and the to expression. BCL-3 by LPS in investigated whether BCL-3 expression is by LPS in macrophages and in TNFα gene transcription. macrophages were with LPS and BCL-3 in nuclear and were over a by to LPS or BCL-3 was in nuclear to LPS increased BCL-3 expression an induction by expression of BCL-3 was also induced by LPS with kinetics of BCL-3 and were in the indicate that the is a not in with that BCL-3 is a T. C. H.C. D. Mol. Cell. Biol. 1993; PubMed Google Scholar, J.H. R. Mol. Cell. Biol. 16: PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). also the kinetics of NF-κB p50 and induction p50 and in the the LPS nuclear p50 to accumulate with LPS-induced expression of p50 is prolonged in with from macrophages (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar). have that BCL-3 and p50 in (13Fujita T. H.C. D. 1993; PubMed Scopus Google Scholar, T. C. H.C. D. Mol. Cell. Biol. 1993; PubMed Google Scholar, G. S. T. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar, N. T. T. T. J. 16: PubMed Scopus Google Scholar, G. S. M. PubMed Scopus Google Scholar). BCL-3 and p50 are present in nuclear from cells to LPS for we whether these two proteins are from and LPS-stimulated macrophages were with for BCL-3 or p50, and the proteins were for the of p50 by In cell p50 was not by the BCL-3 were in nuclear from LPS as by the of p50 in BCL-3 a of the nuclear BCL-3 in LPS-stimulated cells is associated with of BCL-3 the TNFα The of LPS induction that BCL-3 play a role in attenuating TNFα expression. whether BCL-3 negatively TNFα we macrophages with a TNFα (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar) or with of BCL-3 expression activity was over a LPS stimulation of BCL-3 suppressed LPS-induced transcription from the promoter in a inhibiting activity by the of BCL-3 The TNFα promoter three NF-κB sites (κB1, κB2a, and that preferentially bind p50 dimers (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar). whether a these sites (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar) to BCL-3 repression LPS-induced transcription from this promoter in the of BCL-3 was diminished with the promoter BCL-3 to and in fact transcription from the the of BCL-3 to TNFα promoter activity the that NF-κB sites with for p50 dimers. further whether NF-κB sites BCL-3 we the of BCL-3 to transcription from artificial promoters TNFα κB of the or sites of the promoter (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar) were or with the BCL-3 expression expression was following LPS BCL-3 inhibited transcription from both of these and a the NF-κB a site that preferentially (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar), was not by BCL-3 the notion that BCL-3 represses TNFα gene transcription p50 dimers to the κB elements in the promoter. of LPS-induced TNFα in p50 and and p50 null mice have been and immune G. T. S. A. T. A. M. A. Full Text Full Text PDF PubMed Scopus Google Scholar, A. 11: PubMed Scopus Google Scholar, H.C. D. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar). the of these proteins in TNFα expression in we macrophage cell from or control cells by with the which the and PubMed Scopus Google Scholar). The cells were in the of to promote macrophage and was and the cells were further to for macrophage cells. cell from BCL-3 and p50 null mice and and were of the cell surface and that cell to the surface of macrophage cell in a cytokine expression in these the cell by with LPS, over a and TNFα mRNA a protection TNFα mRNA was induced to in with cells In its expression was TNFα elevated in p50-deficient cells in cells to of TNFα mRNA in was to that of cells and TNFα expression in cells was not attenuated, elevated the and that both BCL-3 and p50 to the of TNFα expression induction by BCL-3 IL-10 pro-inflammatory cytokines as as anti-inflammatory factors to modulate immune and IL-10 is a anti-inflammatory cytokine by macrophages R. J. B. J. Med. 1991; PubMed Scopus Google Scholar). investigated whether BCL-3 IL-10 mRNA expression. in IL-10 mRNA were reduced in with cells induction contrast, IL-10 induction in was to that in cells not findings that BCL-3 is required for induction of the IL-10 gene in LPS-stimulated in to its on TNFα expression. of on in that were not by the of cell and to the effects of BCL-3 on cytokine gene expression, we also cytokine transcription in primary macrophages from and BCL-3 null cells were for induction of BCL-3 by of BCL-3 were increased by LPS in macrophages but not in cells. The induction of cytokines by LPS was of and cells that BCL-3 inhibits expression of two pro-inflammatory cytokines and also not In BCL-3 null cells reduced induction of the anti-inflammatory cytokine indicating that BCL-3 expression of this gene. The in primary macrophages the from macrophage cell of p50 and study that BCL-3 promote the and nuclear of p50 homodimers N. T. T. T. J. 16: PubMed Scopus Google Scholar). BCL-3 potentially TNFα gene transcription by the of nuclear p50 homodimers in macrophages. whether BCL-3 the production of p50 we used to p50 dimers in nuclear from and that been with in of p50 homodimers in and cells. p50 dimers were induced with kinetics in both cell the prolonged induction of p50 homodimers in LPS-stimulated macrophages is not on we investigated whether p50 BCL-3 expression. BCL-3 were in from and cell LPS stimulation induction of BCL-3 was reduced in both and nuclear from with cells. A of BCL-3 protein was in the cells but the was that in MΦ, in the nuclear that p50 is required for transcription of the BCL-3 gene or with p50 the BCL-3 protein and also promote its nuclear Although the mechanism to these findings that induction of BCL-3 by LPS is on p50 of the TNFα by BCL-3 repression of transcription involves the recruitment of histone to target promoters by proteins Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). whether in TNFα gene we whether BCL-3-mediated of the promoter is enhanced by expression of The was cells with expression for BCL-3 HDAC-1, and activity was over a following LPS of BCL-3 or suppressed TNFα promoter activity and caused a further in transcription. BCL-3 increased transcription from the promoter κB sites or BCL-3 also the of cells with a reversed BCL-3-mediated of the activity to a over that of the control In contrast, on the with the that a to κB sites in the TNFα promoter and transcription. BCL-3 in cells by of the BCL-3 caused a in the of BCL-3 by with or LPS stimulation the of these cells is and the BCL-3 BCL-3 were increased BCL-3 was with HDAC-1, whether or not the cells were with LPS and and and is that BCL-3 as a of these two whether BCL-3 and in we nuclear from cells that been with LPS or and BCL-3 or control The were for the of by and BCL-3 was in cells with LPS for but not in cells for or The kinetics of are with that BCL-3 is not induced in cells following LPS these that the BCL-3 and proteins a in LPS-stimulated or The for the transcriptional attenuation of TNFα and other pro-inflammatory cytokine that BCL-3 is induced in macrophages by LPS and to pro-inflammatory cytokine gene transcription. LPS not BCL-3 the protein appears with delayed BCL-3 induction the activation of dimers and the that p50 homodimers to over and TNFα to (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar). with the fact that p50 overexpression inhibits transcription from the TNFα promoter (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar, 10Bohuslav J. Kravchenko V.V. Parry G.C. Erlich J.H. Gerondakis S. Mackman N. Ulevitch R.J. J. Clin. Invest. 1998; 102: 1645-1652Crossref PubMed Scopus (243) Google Scholar, 11Kastenbauer S. Ziegler-Heitbrock H.W. Infect. Immun. 1999; 67: 1553-1559Crossref PubMed Google Scholar), that BCL-3 negatively regulate the TNFα gene its with p50 homodimers. In of this overexpression of BCL-3 suppressed LPS-induced transcription from the TNFα promoter in BCL-3 not and the activity of a promoter the three NF-κB sites that preferentially bind p50 homodimers. BCL-3 also two artificial promoter of these p50 sites but not a the which preferentially with the that BCL-3 and p50 in the of LPS-stimulated these findings the that BCL-3 inhibits TNFα transcription to κB sites on the TNFα promoter. Analysis of macrophages from knock-out mice further that p50 and BCL-3 pro-inflammatory cytokine expression. TNFα were induced to in p50 null cells in cells. This elevated expression was also as TNFα in cells expression to In IL-1α mRNA were in cells with cells not indicating that p50 also represses this gene. is that p50 is for LPS-induced transcription of pro-inflammatory cytokine This is that is the NF-κB induced by LPS and is to the of cytokine other NF-κB dimers for to cytokine gene expression. The of BCL-3 on TNFα transcription was that in and was the induction attenuation of TNFα expression was as by the elevated of TNFα mRNA in cells the BCL-3 plays a role in TNFα expression. The inhibitory of p50 on TNFα gene transcription by in and both the LPS induction to BCL-3 expression, and the attenuation BCL-3 that p50 dimers TNFα gene transcription in the of BCL-3 but that BCL-3 p50 indicate that activity is in repression of TNFα, and that is in a nuclear with BCL-3 in LPS-stimulated cells. A study that nuclear are present in cells are by NF-κB associated with the H. May M.J. S. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). findings that LPS stimulation of macrophages causes induction of activating NF-κB which are by p50 dimers associated with BCL-3 and a to transcription of has been that nuclear of p50 homodimers also elevated in LPS a in which cells to of LPS to LPS J. Kravchenko V.V. Parry G.C. Erlich J.H. Gerondakis S. Mackman N. Ulevitch R.J. J. Clin. Invest. 1998; 102: 1645-1652Crossref PubMed Scopus (243) Google Scholar, 11Kastenbauer S. Ziegler-Heitbrock H.W. Infect. Immun. 1999; 67: 1553-1559Crossref PubMed Google Scholar, H.W. J. 1995; 45: Google Scholar, H.W. A. M. T. G. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). macrophages reduced of TNFα and other pro-inflammatory macrophages from p50 null mice are to LPS and are capable of TNFα mRNA with J. Kravchenko V.V. Parry G.C. Erlich J.H. Gerondakis S. Mackman N. Ulevitch R.J. J. Clin. Invest. 1998; 102: 1645-1652Crossref PubMed Scopus (243) Google Scholar). are with that TNFα transcription is prolonged in p50-deficient cells. Although the expression of cytokines was increased in a was of IL-10 by LPS was diminished in primary macrophages and cell that BCL-3 this gene. The transcription factors that regulate the IL-10 gene have not been an site in the human IL-10 promoter is for its activation by LPS in M. M.J. Y. H. J. Immunol. 2000; PubMed Scopus Google Scholar, J. Immunol. 2000; PubMed Scopus Google Scholar, S. D. M. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and a role for in the human gene has also been M. A. T. Ziegler-Heitbrock H.W. J. Immunol. 2000; PubMed Scopus Google Scholar). IL-10 induction was not in p50-deficient macrophages not BCL-3 protein to this promoter. p50 homodimers were induced by LPS with kinetics and to in and macrophages. BCL-3 not regulate the or nuclear of p50 dimers in we such a role for BCL-3 in other cell as has been N. T. T. T. J. 16: PubMed Scopus Google Scholar). a in which BCL-3 the function but not the expression of p50 dimers. the other nuclear and induction of BCL-3 was reduced in macrophages. the mechanism for the expression of BCL-3 is it is that p50 is required for transcriptional of the BCL-3 gene. with this the BCL-3 promoter was to two NF-κB of which is required for activation of the promoter M. T. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the BCL-3 protein p50 dimers are for BCL-3 is not by LPS, and its induction appears to by an factor that is in response to M. and the BCL-3 activity is to TIF by its to TNFα expression and p50 (8Baer M. Dillner A. Schwartz R.C. Sedon C. Nedospasov S. Johnson P.F. Mol. Cell. Biol. 1998; 18: 5678-5689Crossref PubMed Google Scholar) or is a factor to A study found that expression of BCL-3 in cells is induced by such as LPS and that BCL-3 is in D. J. Y. J. Immunol. PubMed Google Scholar). BCL-3 induction by LPS in cells to and the of other has been S. A. Immunol. PubMed Scopus Google Scholar). that LPS BCL-3 in macrophages a soluble factor also the induction of BCL-3 in cells. Although BCL-3 LPS-induced transcription from the TNFα promoter in it not promoter activity to LPS and the effects of BCL-3 were of LPS stimulation for these is that LPS-induced regulate BCL-3, in addition to its expression. BCL-3 was to a T. C. H.C. D. Mol. Cell. Biol. 1993; PubMed Google Scholar, J.H. R. Mol. Cell. Biol. 16: PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), this a by LPS or a factor, that is required for BCL-3 to transcription. with this BCL-3 was to a its induction by LPS or and not the sites of are and further to whether plays a role in BCL-3-mediated transcriptional In we have that BCL-3 and NF-κB p50 the expression of inflammatory in macrophages by transcription of pro-inflammatory cytokine genes such as TNFα, and IL-1β. In BCL-3 expression of the anti-inflammatory IL-10 gene. BCL-3 and p50 play in the immune response to bacterial are to for and NF-κB expression and for and