Phosphatidylinositol 3-kinase activation in normal human B lymphocytes: Differential sensitivity of growth and differentiation to wortmannin

Kjersti M. Aagaard-Tillery, Diane F Jelinek

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)4543-4554
Number of pages12
JournalJournal of Immunology
Volume156
Issue number12
StatePublished - Jun 15 1996

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Phosphatidylinositol 3-Kinase
B-Lymphocytes
Growth
Immunoglobulin D
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Phosphatidylinositol 3-Kinases
wortmannin
Cell Differentiation
CD40 Ligand
Cytokine Receptors

ASJC Scopus subject areas

  • Immunology

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Phosphatidylinositol 3-kinase activation in normal human B lymphocytes : Differential sensitivity of growth and differentiation to wortmannin. / Aagaard-Tillery, Kjersti M.; Jelinek, Diane F.

In: Journal of Immunology, Vol. 156, No. 12, 15.06.1996, p. 4543-4554.

Research output: Contribution to journalArticle

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