Inhibition by glucocorticoid and staurosporine of IL-4-dependent CD23 production in B lymphocytes is reversed on engaging CD40.
IL-4 synergizes with signals delivered through CD40 both for the induction of CD23/Fc epsilon RII expression and for IgE synthesis. Moreover, engagement of CD40 on the B cell surface by MoAb overcomes the ability of interferons, transforming growth factor-beta, or anti-CD19 to inhibit IL-4-dependent change. We now report that occupancy of CD40 relieves potent suppression of IL-4-induced CD23 production by glucocorticoid or the relatively broad-acting kinase inhibitor staurosporine. Interruption of the IL-4 signal was observed with concentrations of staurosporine considered to be selective for protein kinase C (PKC) inhibition (IC50 = 10 nM) but not with genistein or tyrphostins, effective inhibitors of tyrosine kinase activity. On ligation of CD40, staurosporine no longer inhibited the IL-4 signal: at concentrations of between 1 and 20 nM, staurosporine actually increased by as much as 100% the rate of CD23 production stimulated on simultaneous activation through CD40 and IL-4R. Such augmentation was not observed when the more specific PKC inhibitor RO-31-8220 was used; indeed, CD40 engagement was unable to overcome the ability of this inhibitor to block IL-4-promoted CD23 induction (IC50 = 10 microM). Occupancy of CD40 did, however, thwart completely the usual ability of prednisolone to inhibit the IL-4 signal leading to CD23 induction. Activation through CD40 left inhibition of phorbol ester-induced CD23 expression by staurosporine, RO-31-8220, or glucocorticoid unchecked. These findings further highlight the intimate level of cross-talk existing between CD40 and IL-4R on resting B lymphocytes to promote CD23 expression, a phenotypic change which preludes IgE synthesis.
Katira
A
A
Department of Immunology, University of Birmingham, UK.
Knox
K A
KA
Finney
M
M
Michell
R H
RH
Wakelam
M
M
Gordon
J
J
D000470:Alkaloids / Q000494:pharmacology*; D015703:Antigens, CD / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D019013:CD40 Antigens; D002478:Cells, Cultured; D019833:Genistein; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D007529:Isoflavones / Q000494:pharmacology; D011239:Prednisolone / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000502:physiology; D017455:Receptors, IgE / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D019311:Staurosporine
D000470:Alkaloids; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D007211:Indoles; D007529:Isoflavones; D011956:Receptors, Cell Surface; D017455:Receptors, IgE; D011994:Recombinant Proteins; D015847:Interleukin-4; D011239:Prednisolone; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D019311:Staurosporine; C064758:Ro 31-8220