IFN-gamma and prostaglandin E2 inhibit IL-4-induced expression of Fc epsilon R2/CD23 on B lymphocytes through different mechanisms without altering binding of IL-4 to its receptor.
Human rIL-4 specifically induces the expression of the low affinity receptor for IgE (Fc epsilon R2/CD23) on normal B cells and on the Burkitt lymphoma cell line Jijoye. IL-4 does not induce the generation of the second messenger cAMP in Jijoye cells. PGE2 (at 10(-7) M) was found to inhibit by 50% the IL-4 mediated Fc epsilon R2/CD23 induction on Jijoye cells. The PGE2 half maximum inhibitory concentration (1 nM) was comparable to that inducing a half maximal increase of intracellular cAMP (4nM PGE2). 8-bromo-cAMP (10(-3) M), forskolin (10(-5) M), and cholera toxin (100 ng/ml), which increase intracellular cAMP levels, also inhibited by 40 to 80% the IL-4 induced Fc epsilon R2/CD23 expression on Jijoye cells. PGE2 8-bromo-cAMP, forskolin, and cholera toxin also inhibited the IL-4-induced Fc epsilon R2/CD23 expression on normal B lymphocytes. Taken together these data suggest that PGE2 inhibits the IL-4 induced Fc epsilon R2/CD23 through an increase of intracellular cAMP. In contrast, IFN-gamma, which strongly inhibits IL-4-mediated Fc epsilon R2/CD23 expression on Jijoye cells, did not increase intracellular cAMP levels and thus probably acts through another mechanism. IFN-gamma and PGE2 did not inhibit binding of IL-4 to its receptor. It could be excluded that IFN-gamma and PGE2 were acting via an alteration/desensitization of the IL-4R inasmuch as 24 h pre-incubation of Jijoye cells with these agents affected neither the affinity of 125I-IL-4 for its receptor (Kd = 0.8 to 1.5 x 10(-10) M) nor the maximal number of binding sites per Jijoye cells (Bmax = 390 to 550). Furthermore, IFN-gamma and PGE2 did not affect the internalization and degradation of 125I-IL-4. These data demonstrate that PGE2 and IFN-gamma inhibit the IL-4-mediated induction of Fc epsilon R2/CD23 on B lymphocytes via different mechanisms that do not alter the interaction of IL-4 with its receptor.
Galizzi
J P
JP
UNICET, Laboratory for Immunological Research, Dardilly, France.
Cabrillat
H
H
Rousset
F
F
Ménétrier
C
C
de Vries
J E
JE
Banchereau
J
J
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D001667:Binding, Competitive; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D015232:Dinoprostone / Q000494:pharmacology*; D006801:Humans; D007073:Immunoglobulin E / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D015847:Interleukin-4; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000378:metabolism; D007457:Iodine Radioisotopes; D011961:Receptors, Fc / Q000096:biosynthesis / Q000378:metabolism*; D017455:Receptors, IgE; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000187:drug effects*
D000944:Antigens, Differentiation, B-Lymphocyte; D007378:Interleukins; D007457:Iodine Radioisotopes; D011961:Receptors, Fc; D017455:Receptors, IgE; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D005576:Colforsin; D015847:Interleukin-4; C015722:8-bromo-2'-AMP; D007073:Immunoglobulin E; D000249:Adenosine Monophosphate; D007371:Interferon-gamma; D002772:Cholera Toxin; D000242:Cyclic AMP; D015232:Dinoprostone