Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in normal, self-renewing B-1 cells but only inducibly expressed in conventional B lymphocytes

被引:129
作者
Karras, JG
Wang, ZH
Huo, L
Howard, RG
Frank, DA
Rothstein, TL
机构
[1] BOSTON UNIV,MED CTR,DEPT MED,BOSTON,MA 02118
[2] BOSTON UNIV,MED CTR,DEPT MICROBIOL,BOSTON,MA 02118
[3] BOSTON UNIV,MED CTR,EVANS MEM DEPT CLIN RES,BOSTON,MA 02118
[4] DANA FARBER CANC INST,DIV HEMATOL MALIGNANCIES,BOSTON,MA 02115
关键词
D O I
10.1084/jem.185.6.1035
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Cytokine and growth factor receptor engagement leads to the rapid phosphorylation and activation of latent, cytosolic signal transducers and activators of transcription (STAT) proteins, which then translocate to the nucleus where they regulate transcriptional events from specific promoter sequences. STAT3 expression in particular has been associated with Abl, Src, and HTLV-1 transformation of normal cells. B-1 lymphocytes are self-renewing, CD5(+) B cells that display a propensity for malignant transformation and are the normal counterpart to human chronic lymphocytic leukemias. Further, B-1 cells are characterized by aberrant intracellular signaling, including hyperresponsiveness to phorbol ester PKC agonists. Here we demonstrate that B-1 lymphocytes constitutively express nuclear activated STAT3, which is not expressed by unmanipulated conventional (B-2) lymphocytes. In contrast, STAT3 activation is induced in B-2 cells after antigen receptor engagement in a delayed fashion (after 3 h). Induction of STAT3 is inhibited by both the serine/threonine protein kinase inhibitor H-7 and the immunosuppressive drug rapamycin and requires de novo protein synthesis, demonstrating novel coupling between sig and STAT proteins that differs from the classical paradigm for STAT induction by cytokine receptors. The inability of prolonged stimulation of conventional B-2 cells with anti-Ig, a treatment sufficient to induce CD5 expression, to result in sustained STAT3 activation suggests that STAT3 is a specific nuclear marker for B-1 cells. Thus, STAT3 may play a role in B cell antigen-specific signaling responses, and its constitutive activation is associated with a normal cell population exhibiting intrinsic proliferative behavior.
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页码:1035 / 1042
页数:8
相关论文
共 43 条
[1]   MOLECULAR-CLONING OF APRF, A NOVEL IFN-STIMULATED GENE FACTOR-3 P91-RELATED TRANSCRIPTION FACTOR INVOLVED IN THE GP130-MEDIATED SIGNALING PATHWAY [J].
AKIRA, S ;
NISHIO, Y ;
INOUE, M ;
WANG, XJ ;
WEI, S ;
MATSUSAKA, T ;
YOSHIDA, K ;
SUDO, T ;
NARUTO, M ;
KISHIMOTO, T .
CELL, 1994, 77 (01) :63-71
[2]   CHARACTERIZATION OF A PATHWAY FOR CILIARY NEUROTROPHIC FACTOR SIGNALING TO THE NUCLEUS [J].
BONNI, A ;
FRANK, DA ;
SCHINDLER, C ;
GREENBERG, ME .
SCIENCE, 1993, 262 (5139) :1575-1579
[3]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[4]   B-LYL CELLS - IMMORTAL LY-1+ LYMPHOCYTE-B CELL-LINES SPONTANEOUSLY ARISING IN MURINE SPLENIC CULTURES [J].
BRAUN, J ;
CITRI, Y ;
BALTIMORE, D ;
FOROUZANPOUR, F ;
KING, L ;
TEHERANIZADEH, K ;
BRAY, M ;
KLIEWER, S .
IMMUNOLOGICAL REVIEWS, 1986, 93 :5-21
[5]   MONOREACTIVE HIGH-AFFINITY AND POLYREACTIVE LOW AFFINITY RHEUMATOID FACTORS ARE PRODUCED BY CD5+ B-CELLS FROM PATIENTS WITH RHEUMATOID-ARTHRITIS [J].
BURASTERO, SE ;
CASALI, P ;
WILDER, RL ;
NOTKINS, AL .
JOURNAL OF EXPERIMENTAL MEDICINE, 1988, 168 (06) :1979-1992
[6]   INFREQUENT NORMAL LYMPHOCYTES-B EXPRESS FEATURES OF B-CHRONIC LYMPHOCYTIC-LEUKEMIA [J].
CALIGARISCAPPIO, F ;
GOBBI, M ;
BOFILL, M ;
JANOSSY, G .
JOURNAL OF EXPERIMENTAL MEDICINE, 1982, 155 (02) :623-628
[7]  
Cao XM, 1996, MOL CELL BIOL, V16, P1595
[8]   JAK-STAT PATHWAYS AND TRANSCRIPTIONAL ACTIVATION IN RESPONSE TO IFNS AND OTHER EXTRACELLULAR SIGNALING PROTEINS [J].
DARNELL, JE ;
KERR, IM ;
STARK, GR .
SCIENCE, 1994, 264 (5164) :1415-1421
[9]   INDUCTION OF THE TRANSCRIPTION FACTORS NF-KB, AP-1 AND NF-AT DURING B-CELL STIMULATION THROUGH THE CD40 RECEPTOR [J].
FRANCIS, DA ;
KARRAS, JG ;
KE, XY ;
SEN, R ;
ROTHSTEIN, TL .
INTERNATIONAL IMMUNOLOGY, 1995, 7 (02) :151-161
[10]   INTERLEUKIN-2 SIGNALING INVOLVES THE PHOSPHORYLATION OF STAT PROTEINS [J].
FRANK, DA ;
ROBERTSON, MJ ;
BONNI, A ;
RITZ, J ;
GREENBERG, ME .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (17) :7779-7783