title: Concentration-dependent bifunctional effect of TGF-beta 1 on immunoglobulin production: a role for Smad3 in IgA production in vitro.
abstract: Injury to the liver results in rapid induction of transforming growth factor-beta1 (TGF-beta(1)) consistent with a role for TGF-beta(1) in repairing damaged tissue. In addition to its ubiquitous role in injury repair, TGF-beta(1) is also well established as a critical regulator of immune homeostasis; however, its mechanisms of action remain enigmatic. We have previously demonstrated that the hepatotoxic chlorinated hydrocarbon, carbon tetrachloride, suppresses helper T-lymphocyte function in a TGF-beta(1)-dependent manner. Here, we report that, in opposition to its immunosuppressive effects at picomolar concentrations, femtomolar concentrations of TGF-beta(1) augment T cell-dependent anti-sRBC IgM antibody forming cell (AFC) and T cell-independent DNP-Ficoll-induced AFC responses. These data support a concentration-dependent bifunctional effect by TGF-beta(1) on humoral immune responses in vitro. We further investigated a putative mechanistic role for Smad3, an intracellular mediator of TGF-beta(1) signaling, in propagating the inhibitory effects of TGF-beta(1) on humoral immune responses. Relative to wild type littermates, splenocytes from mice homologous for a null mutation in the gene encoding the TGF-beta receptor-activated Smad3 (Smad3(Exon8-/-)) were less sensitive to inhibition by TGF-beta(1) following anti-sRBC- and LPS-sensitization in vitro. In agreement, inhibition of IgM protein production by TGF-beta(1) was also dampened in LPS-sensitized Smad3(Exon8-/-) splenic B cells. Moreover, stimulation of IgA by TGF-beta(1) was abrogated in LPS-sensitized Smad3(Exon8-/-) splenocytes suggesting an additional role for Smad3 in regulating IgA production in vitro. Our results suggest that the effects of TGF-beta(1) on humoral immune responses fundamentally differ in a concentration-dependent manner and are mediated, in part, through Smad3 signaling.
authors.affiliation: Department of Pharmacology and Toxicology, 315 National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Susan C
authors.initials: SC
authors.lastname: McKarns
authors.forename: John J
authors.initials: JJ
authors.lastname: Letterio
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D000917:Antibody Formation; D000921:Antibody-Producing Cells / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D005362:Ficoll / Q000031:analogs & derivatives* / Q000494:pharmacology; D017353:Gene Deletion; D015870:Gene Expression / Q000235:genetics; D007070:Immunoglobulin A / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000276:immunology* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: C031007:DNP-Ficoll; D007070:Immunoglobulin A; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D005362:Ficoll