IL-4 counteracts anti-mu-induced human B cell proliferation: involvement of a cAMP-dependent inhibitory pathway.
In this report we show that IL-4 inhibits DNA synthesis induced by stimulation of human B cells with mitogenic doses of either soluble anti-mu mAb DA44 or phorbol ester. In contrast, earlier steps of anti-mu-induced B cell stimulation, such as RNA synthesis, CD23 expression and IL-6 production, were not inhibited but rather increased in the presence of IL-4. From these results, IL-4 appears therefore to exert two opposite effects on DA44 anti-mu mAb-induced human B cell activation: early steps are stimulated, and later steps inhibited. The results of kinetic analysis were consistent with this model. The inhibitory activity of IL-4 required an active cAMP-dependent pathway since IL-4-mediated inhibition of anti-mu-induced B cell proliferation was abolished in the presence of two specific inhibitors of the cAMP pathway (H8 and 2',5'-dideoxyadenosine which are specific for cAMP-dependent protein kinase and adenylate cyclase respectively). Furthermore, IL-4 induced a delayed and prolonged increase in intracellular cAMP concentrations (observed between 4 and 48 hours of culture), and this strongly suggests that the late inhibitory effects of IL-4 is cAMP-dependent. Moreover, this delayed IL-4-mediated cAMP production is probably sufficient to prevent anti-mu induced DNA synthesis since addition of the cAMP agonist forskolin on day 1 or 2 of culture also suppresses the anti-mu-mediated B cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)
Taieb
J
J
Inserm U 131, Clamart, France.
Leca
G
G
Auffredou
M T
MT
Galanaud
P
P
Vazquez
A
A
D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology / Q000502:physiology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D002478:Cells, Cultured; D002648:Child; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D004261:DNA Replication / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D014066:Palatine Tonsil / Q000276:immunology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000187:drug effects; D011961:Receptors, Fc / Q000276:immunology / Q000502:physiology*; D017455:Receptors, IgE; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D015850:Interleukin-6; D011961:Receptors, Fc; D017455:Receptors, IgE; D011994:Recombinant Proteins; D005576:Colforsin; D015847:Interleukin-4; D015240:Phorbol 12,13-Dibutyrate; D012313:RNA; D000242:Cyclic AMP; D013936:Thymidine