HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhang, H. Articles by Zhang, J. Search for Related Content PubMed PubMed Citation Articles by Zhang, H. Articles by Zhang, J.

A Role for cFLIP in B Cell Proliferation and Stress MAPK Regulation¹

Haibing Zhang^*, Stephen Rosenberg^*, Francis J. Coffey^*, You-Wen He, Timothy Manser^*, Richard R. Hardy and Jianke Zhang^2,*

^* Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; Department of Immunology, Duke University, Durham, NC 27710; and Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, PA 19111

Fas/Apo-1 signals through the FADD (Fas-associated death domain) adaptor protein, which recruits and activates the apical caspase 8 and leads to apoptosis. Cellular FLIP (cFLIP) is a homolog of caspase 8 and is also capable of binding to FADD. Previous studies suggest that cFLIP could either enhance or inhibit apoptosis and lead to NF-B and Erk1/2 activation. Like FADD or caspase 8 deficiency, a lack of cFLIP disrupts embryogenesis and T cell proliferation. It has been demonstrated that B cells lacking either FADD or caspase 8 were defective in both Fas-induced apoptosis and TLR-induced proliferation, which indicates that these death-inducing proteins have an additional role in regulating innate immunity. To analyze the function of cFLIP in B cells, conditional deletion of cFLIP was induced by using CD19^Cre. The resulting B cell-specific cFLIP-deficient mice were found to have reduced numbers of peripheral B cells that were hypersensitive to Fas-induced apoptosis and impaired in proliferation induced by TLRs and the BCR. Furthermore, there was aberrant expression of costimulatory proteins and activation markers in cFLIP-deficient B cells. Whereas LPS-induced activation of NF-B and Erk1/2 appears to be unaffected, p38 and Jnk were spontaneously activated and hyperinduced in cFLIP-deficient B cells. Therefore, these data revealed novel functions of cFLIP in B cells.

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 study was supported in part by National Institutes of Health grants (CA95454 and AI076788) and a Thomas Jefferson University Pilot grant (920012) to J.Z.

² Address correspondence and reprint requests to Dr. Jianke Zhang, Kimmel Cancer Center, Department of Microbiology and Immunology, Thomas Jefferson University, 233 S. 10th Street, Room 731 BLSB, Philadelphia, PA 19107. E-mail address: jzhang{at}mail.jci.tju.edu

³ Abbreviations used in this paper: DR, death receptor; cFLIP, cellular FLIP; FADD, Fas-associated death domain; NP, nitrophenol; PI, propidium iodide; 7AAD, 7-aminoactinomycin D; TNP, trinitrophenol.