Carbon tetrachloride suppresses T-cell-dependent immune responses by induction of transforming growth factor-beta 1.
In vivo exposure of B6C3F1 mice to the hepatotoxic chlorinated hydrocarbon, CCl4, suppresses T-cell-dependent humoral immune responses to sRBC. In the present studies, separation-crossover-reconstitution experiments with spleen cell subpopulations isolated from vehicle and CCl4-treated mice (500 mg/kg/day for 7 days) indicate that T-cells are the primary immunologic cell-type altered following CCl4 exposure. Despite suppression of T-cell activity, Con A-activated spleen cell supernatants from CCl4-treated mice produced greater amounts of biologically active IL-2 than untreated spleen cells. Furthermore, Con A-induced upregulation of the p55 subunit of the IL-2 receptor was not altered in spleen cells from CCl4-treated mice. The mediator of immune suppression is a serum-borne factor induced 48 hr following a single exposure to CCl4. Sera isolated from mice treated with CCl4 for 7 days (500 mg/kg/day) or 48 hr following a single exposure (1000 mg/kg) were found to possess high concentrations of TGF-beta 1. Direct addition studies demonstrated that T-cell-dependent AFC responses are more sensitive to suppression by TGF-beta 1 than are T-cell-independent responses. Finally, incubation of sera from CCl4-treated mice with TGF-beta 1-neutralizing mAb reversed the immune suppression associated with this serum. These results demonstrate that CCl4-induced immune suppression is at least partially mediated by induction of TGF-beta 1.
Delaney
B
B
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298.
Strom
S C
SC
Collins
S
S
Kaminski
N E
NE
D000818:Animals; D000921:Antibody-Producing Cells / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000633:toxicity*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D008815:Mice, Inbred Strains; D015375:Receptors, Interleukin-2 / Q000187:drug effects; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000187:drug effects*
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D002251:Carbon Tetrachloride