Phorbol ester, prostaglandin E2, forskolin and okadaic acid differentially modulate interleukin-4-versus interleukin-2-dependent immunoglobulin induction in human cellular models, in contrast to other selected modifiers of cellular activation.
Interleukin 2 (IL2) and 4 (IL4) are the most important mediators for immunoglobulin (Ig) synthesis of human B lymphocytes. There is no obvious difference with regard to Ig isotypes induced by either lymphokine except for IgE: only IL4 induces this allergic antibody type. Monoclonal anti-CD40 antibodies enhance both IL2- and IL4-dependent Ig induction. Searching for drugs which may inhibit induction of IgE but not of rather non-pathogenic immunoglobulins, we selected commercial compounds which are commonly used as probes for transmembrane signalling pathways in other cellular systems. They included modulators of protein kinase C and intracellular calcium, inducers of cAMP, and inhibitors of protein tyrosine kinase, protein serine/threonine phosphatases and phosphodiesterases. The data presented suggest that IL2- and IL4-mediated B cell activation can be differentially modulated. Phorbol ester at non-cell-toxic doses inhibited IL4- but not IL2-dependent Ig induction. Prostaglandin E2 potently enhanced IgE production stimulated with IL4 alone but was inhibitory in the presence of anti-CD40 as a co-stimulatory signal. IgG1 responses elicited with IL2 plus anti-CD40, in contrast, were not affected. All other compounds did not discriminate between IL2- versus IL4-mediated Ig induction.
Armerding
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Sandoz Forschungsinstitut, Vienna, Austria.
Hren
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D000911:Antibodies, Monoclonal; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D005576:Colforsin / Q000276:immunology*; D015232:Dinoprostone / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D004988:Ethers, Cyclic / Q000276:immunology*; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D007136:Immunoglobulins / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D013755:Tetradecanoylphorbol Acetate
D000911:Antibodies, Monoclonal; D004988:Ethers, Cyclic; D007074:Immunoglobulin G; D007136:Immunoglobulins; D007376:Interleukin-2; D007378:Interleukins; D005576:Colforsin; D019319:Okadaic Acid; D015847:Interleukin-4; D007073:Immunoglobulin E; D010749:Phosphoprotein Phosphatases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate