Journal Article

TCDD-Mediated Suppression of the <i>In Vitro</i> Anti-Sheep Erythrocyte IgM Antibody Forming Cell Response is Reversed by Interferon-Gamma

Colin M. North, Byung-Sam Kim, Neil Snyder, Robert B. Crawford, Michael P. Holsapple and Norbert E. Kaminski

in Toxicological Sciences

Volume 107, issue 1, pages 85-92
Published in print January 2009 | ISSN: 1096-6080
Published online October 2008 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfn223
TCDD-Mediated Suppression of the In Vitro Anti-Sheep Erythrocyte IgM Antibody Forming Cell Response is Reversed by Interferon-Gamma

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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-γ) 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-γ attenuates suppression of humoral immune responses by TCDD. In fact, concomitant addition of IFN-γ (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-γ 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-γ was added within 2 h of TCDD treatment. mRNA levels of the IgM components, immunoglobulin κ light chain, immunoglobulin μ heavy chain, and immunoglobulin J-chain were significantly decreased by TCDD treatment, an effect that was completely reversed by IFN-γ (100 U/ml) cotreatment. Further studies showed that IFN-α, IFN-β, and IFN-γ 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-γ prevents TCDD-mediated suppression of the IgM AFC response in a concentration- and time-related manner by altering transcriptional effects associated with TCDD treatment.

Keywords: TCDD; immunotoxicology; IgM, in vitro; IFN-γ

Journal Article.  5118 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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