CROSS-LINKING CD40 ON B-CELLS PREFERENTIALLY INDUCES STRESS-ACTIVATEDPROTEIN-KINASES RATHER THAN MITOGEN-ACTIVATED PROTEIN-KINASES

The B cell-associated surface molecule CD40 plays a key role in T cell -dependent B cell maturation, as individuals with defects in either CD 40 or its ligand are impaired in immunoglobulin isotype class switchin g and germinal center formation, CD40 signaling activates downstream e ffecters, including the tyrosine protein kinase, Lyn, the phosphatidyl inositol-3-kinase (PI-3 kinase), and the transcription factor, NF-kapp a B. In this study, we demonstrate that stress-activated protein kinas es (SAPK) are activated after CD40 cross-linking on various B cell lin es or human tonsillar B cells. The activation is rapid and transient a nd is mediated through a cyclosporin A-insensitive pathway, Furthermor e, this signaling pathway appears not to rely on protein kinase C, Whi le CD40 ligation strongly activates the SAPKs (up to 25-fold), it does not affect members of the mitogen-activated protein kinase family (MA PK; ERK1 and ERK2), Consistent with these data, CD40 signals up-regula te c-jun but not c-fos mRNA and alter the transcription factor ATF2 bu t not the Raf-1 protein, In summary, CD40 signaling preferentially ind uces SAPK but not MAPK.