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B Cell Receptor Cross-Talk: Exposure to Lipopolysaccharide Induces an Alternate Pathway for B Cell Receptor-Induced ERK Phosphorylation and NF-B Activation¹

John R. Dye^*,, Arkadiy Palvanov^¶, Benchang Guo^,,¶ and Thomas L. Rothstein^2,,,,¶

Departments of ^* Pathology, Medicine, and Microbiology, Boston University School of Medicine, Boston, MA 02118; Immunobiology Unit, Evans Memorial Department of Clinical Research, Boston University Medical Center, Boston, MA 02118; and ^¶ Center for Oncology and Cell Biology, Feinstein Institute for Medical Research, Manhasset, NY 11030

BCR signaling in naive B cells depends on the function of signalosome mediators; however, prior engagement of CD40 or of IL-4R produces an alternate signaling pathway in which Bruton’s tyrosine kinase, PI3K, phospholipase C2, and protein kinase C are no longer required for BCR-induced downstream events. To explore the range of mediators capable of producing such an alternate pathway for BCR signaling, we examined the TLR4 agonist, LPS. B cell treatment with LPS at relatively low doses altered subsequent BCR signaling such that ERK phosphorylation and NF-B activation occurred in a PI3K-independent manner. This effect of LPS extended to MEK phosphorylation and IB degradation, and it developed slowly over a period of 16–24 h. The involvement of TLRs is suggested by similar effects observed with a structurally distinct TLR agonist, PAM3CSK4 and by the need for MyD88 for induction of alternate BCR signaling by LPS. Thus, LPS-mediated TLR engagement produces an alternate pathway for BCR-triggered signal propagation that differs from the classical, signalosome-dependent pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by U.S. Public Health Service Grant AI40181 awarded by the National Institutes of Health. J.R.D. is the recipient of a Karen Grunebaum Fellowship in Cancer Research.

² Address correspondence and reprint requests to Dr. Thomas L. Rothstein, Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030. E-mail address: tr{at}nshs.edu

³ Abbreviations used in this paper: Akt, cellular homology of the AKR mouse T cell lymphoma-transforming retrovirus; PKC, protein kinase C; PLC, phospholipase C; PAM3CSK4, N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)propyl]-[R]-cysteinyl-[S]-seryl- [S]-lysyl-[S]-lysyl-[S]-lysyl-[S]-lysine · 3HCl; anti-Ig, F(ab')₂ goat anti-mouse IgM; pERK, phospho-ERK.

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