Abstract
Suppression of humoral immune responses by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been well established to require the aryl hydrocarbon receptor; however, the downstream mechanisms for this immunotoxic response remain poorly understood. Based on evidence demonstrating that primary hepatocytes pretreated with interferon-gamma (IFN-gamma) exhibited decreased induction of cytochrome P450 1A1 (CYP1A1) by TCDD, and that serum factors alter the sensitivity of the in vitro T-cell-dependent IgM antibody forming cell (AFC) response, it was hypothesized that IFN-gamma attenuates suppression of humoral immune responses by TCDD. In fact, concomitant addition of IFN-gamma (100 U/ml) produced a concentration-related attenuation of TCDD-mediated suppression of the anti-sheep erythrocyte (anti-sRBC) IgM AFC response. Time-of-addition studies performed by adding 100 U/ml IFN-gamma at 0, 1, 2, 4, 12, 24, 48, and 72 h post-TCDD showed that suppression of the AFC response was prevented only when IFN-gamma was added within 2 h of TCDD treatment. mRNA levels of the IgM components, immunoglobulin kappa light chain, immunoglobulin mu heavy chain, and immunoglobulin J-chain were significantly decreased by TCDD treatment, an effect that was completely reversed by IFN-gamma (100 U/ml) cotreatment. Further studies showed that IFN-alpha, IFN-beta, and IFN-gamma significantly attenuate TCDD-induced increases in CYP1A1 mRNA levels to varying degrees, but concentrations as high as 1000 U/ml of type I IFNs did not reverse the effect of TCDD on the anti-sRBC IgM AFC response. In summary, IFN-gamma prevents TCDD-mediated suppression of the IgM AFC response in a concentration- and time-related manner by altering transcriptional effects associated with TCDD treatment.