Phosphatidylinositol 3-kinase activation in normal human B lymphocytes.
A variety of signals, mediated via either the B cell Ag receptor (BCR), or non-BCR molecules such as CD40 or cytokine receptors, have been shown to be crucial for the regulation of B cell survival, growth, and differentiation. Although it is clear that a variety of signaling pathways can be activated in B cells in a stimulus-dependent manner, it remains unknown whether differential activation of these signaling pathways is the underlying mechanism controlling B cell fate, i.e., growth vs differentiation. Initial studies reported here indicated that stimulation of highly purified peripheral blood B cells with the polyclonal B cell activators Staphylococcus aureus and CD40 ligand (CD40L) resulted in the rapid induction of phosphatidylinositol 3-kinase (PI 3-kinase) activity. Moreover, pretreatment of B cells with wortmannin, a specific inhibitor of PI 3-kinase, resulted in a complete block in induction of PI 3-kinase activity. The effects of wortmannin, as well as a second PI 3-kinase inhibitor, LY294002, on the induction of both B cell growth and differentiation were therefore investigated. Although these PI 3-kinase inhibitors variably inhibited B cell DNA synthesis in a stimulus-dependent manner, both drugs effected a near-complete block of the ability of each of these stimuli to induce Ig production. Furthermore, separation of B cells into naive IgD+ and postswitch IgD- B cells failed to reveal differential sensitivity of these populations to wortmannin. These results suggest that activation of PI 3-kinase, or other wortmannin- and LY294002-sensitive targets, is a crucial event that occurs during the differentiation of normal human B lymphocytes. The differential sensitivity of B cell responses to inhibitors of PI 3-kinase supports the notion that distinct signal transduction pathways are involved in differentiation vs proliferation of normal human B lymphocytes.
Aagaard-Tillery
K M
KM
Department of Immunology, Mayo Clinic/Foundation, Rochester, MN 55905, USA.
Jelinek
D F
DF
D000328:Adult; D000730:Androstadienes / Q000494:pharmacology; D016175:B-Lymphocyte Subsets / Q000502:physiology; D001402:B-Lymphocytes / Q000201:enzymology*; D019013:CD40 Antigens / Q000502:physiology; D023201:CD40 Ligand; D002454:Cell Differentiation; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007072:Immunoglobulin D / Q000032:analysis; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D015398:Signal Transduction; D000077191:Wortmannin
D000730:Androstadienes; D019013:CD40 Antigens; D002867:Chromones; D004791:Enzyme Inhibitors; D007072:Immunoglobulin D; D008562:Membrane Glycoproteins; D009025:Morpholines; D011947:Receptors, Antigen, B-Cell; D023201:CD40 Ligand; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D000077191:Wortmannin