2,3,7,8-Tetrachlorodibenzo-p-dioxin stimulation of tyrosine phosphorylation in B lymphocytes: potential role in immunosuppression.
The prototype halogenated aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is carcinogenic and toxic in experimental animals. At the cellular level, TCDD toxicity is often expressed as an inhibition or alteration in normal cell maturation. In this respect, we and others have demonstrated that exposure of experimental animals to TCDD causes immunosuppression, including inhibition of B lymphocyte maturation and antibody synthesis. Although the immunological effects of TCDD are well described, little is known about its mechanism of action. In the present studies, it was found that TCDD increases membrane protein phosphorylation, which is, in part, associated with tyrosine-specific phosphorylation in B lymphocytes. This increase in phosphorylation occurred within minutes following TCDD treatment and was not associated with protein kinase C. The increase in tyrosine kinase by TCDD appears to be primarily due to de novo synthesis of new protein, because the protein synthesis inhibitors puromycin and cycloheximide, as well as the transcriptional inhibitor actinomycin D, partially inhibited the effect, although increased activity of preexisting protein cannot be fully dismissed. The dose response for increased phosphorylation by TCDD was identical to that we previously reported for inhibition of antibody synthesis, suggesting that immunosuppression by TCDD may be expressed through alterations in regulatory processes controlled by tyrosine kinases. These studies are discussed in terms of the potential role of TCDD-induced tyrosine phosphorylation in immunosuppression.
Clark
G C
GC
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Blank
J A
JA
Germolec
D R
DR
Luster
M I
MI
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation; D007165:Immunosuppression Therapy; D008565:Membrane Proteins / Q000097:blood; D051379:Mice; D008815:Mice, Inbred Strains; D010766:Phosphorylation; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000097:blood* / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000378:metabolism; D013268:Stimulation, Chemical; D013997:Time Factors; D014443:Tyrosine / Q000097:blood
D008565:Membrane Proteins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases