Mechanisms of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced disruption of B-lymphocyte signaling in the mouse: a current perspective.
TCDD treatment of B cells appears to induce kinase activity (i.e., possibly tyrosine kinases) as well as increases in resting intracellular calcium concentration, in the absence of any other stimuli. These activities, either together or apart, may result in an inappropriate activational response, rendering the B cell less responsive to stimulation by antigen or mitogens. TCDD appears to selectively inhibit B-cell responses that involve demonstrable calcium involvement. The functional defect caused by TCDD is most likely downstream of phospholipase C, since the B-cell proliferative response to PMA plus ionomycin is strongly inhibited by TCDD. It remains unclear how an elevation of intracellular calcium fits in with the described profile of activity for TCDD on B cells. Although it seems probable that disrupted calcium homeostasis would result in changes in membrane permeability, ionic fluxes are poorly understood in general, and in B cells, there is no current evidence that TCDD exposure can induce calcium-activated apoptosis. Furthermore, it is not known if increases in intracellular calcium are associated with the pattern of tyrosine phosphorylation reported for TCDD in B cells. Since changes in calcium have also been observed in other tissues, our results support a role for alteration of calcium homeostasis as a common mechanism for TCDD toxicity. It appears that for complex biological responses to occur, such as proliferation, or the manufacture and secretion of proteins, several signal transduction pathways must converge. The ultimate outcome of these information inputs likely depends upon the strength of the individual stimuli, the integrative capabilities of the combined stimuli, and the maturational stage of the cell.(ABSTRACT TRUNCATED AT 250 WORDS)
Karras
J G
JG
Medical College of Virginia/Virginia Commonwealth University, Richmond.
Holsapple
M P
MP
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000633:toxicity; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011494:Protein Kinases / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
D007166:Immunosuppressive Agents; D000072317:Polychlorinated Dibenzodioxins; D011494:Protein Kinases; D002118:Calcium