ToxSci Advance Access originally published online on October 22, 2008
Toxicological Sciences 2009 107(1):85-92; doi:10.1093/toxsci/kfn223
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TCDD-Mediated Suppression of the In Vitro Anti-Sheep Erythrocyte IgM Antibody Forming Cell Response is Reversed by Interferon-Gamma
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* Department of Pharmacology and Toxicology
Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
Department of Biological Sciences and Immunomodulation Research Center, University of Ulsan, Ulsan, South Korea
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298
¶ ILSI Health and Environmental Sciences Institute, Washington, DC 20005
2 To whom correspondence should be addressed at 315 National Food Safety & Toxicology Center, Michigan State University, East Lansing, MI 48824. Fax: 517-432-3218. E-mail: kamins11{at}msu.edu
Received August 1, 2008; accepted October 9, 2008
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Abstract |
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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-
) 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- attenuates suppression of humoral immune responses by TCDD. In fact, concomitant addition of IFN- (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- 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- was added within 2 h of TCDD treatment. mRNA levels of the IgM components, immunoglobulin 
light chain, immunoglobulin µ heavy chain, and immunoglobulin J-chain were significantly decreased by TCDD treatment, an effect that was completely reversed by IFN- (100 U/ml) cotreatment. Further studies showed that IFN-
, IFN-β, and IFN- 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- prevents TCDD-mediated suppression of the IgM AFC response in a concentration- and time-related manner by altering transcriptional effects associated with TCDD treatment.
Key Words: TCDD; immunotoxicology; IgM, in vitro; IFN-.
1 These authors contributed equally to this work.