Interleukin-12 differentially regulates expression of IFN-γ and interleukin-2 in human T lymphoblasts

被引:12
作者
Dickensheets, HL [1 ]
Freeman, SL [1 ]
Donnelly, RP [1 ]
机构
[1] US FDA, Ctr Biol Evaluat & Res, Div Cytokine Biol, Rockville, MD 20852 USA
关键词
D O I
10.1089/10799900050163271
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Interleukin-12 (IL-12) is known to upregulate expression of interferon-gamma (IFN-gamma) by activated T cells. However, the effects of IL-12 on production of other Th1-type cytokines are less well defined. In this study, we examined the effects of IL-12 on expression of several cytokines, including IFN-gamma, IL-2, tumor necrosis factor-a (TNF-alpha), and IL-10, by primary human CD3(+) T cells. Although purified resting T cells were largely nonresponsive to IL-12 stimulation, anti-CD3-activated T cell blasts were strongly responsive, as demonstrated by the ability of IL-12 to induce Stat4 DNA-binding activity. Restimulation of T lymphoblasts on immobilized anti-CD3 monoclonal antibodies (mAb) induced rapid expression of TNF-alpha mRNA and more gradual increases in mRNA levels for IL-2, IFN-gamma, and IL-10. IL-12 markedly upregulated expression of IFN-gamma and IL-10 but downregulated expression of IL-2 in a dose-dependent and time-dependent manner. The levels of IL-2 produced by IL-12-treated T cells correlated inversely with the levels of IL-10. Moreover, neutralization of IL-10 activity with anti-IL-10 antibodies normalized IL-2 production by IL-12-treated T cells, confirming that the inhibition of IL-2 production by IL-12 was IL-10 mediated. Thus, IL-12 amplified expression of IFN-gamma and IL-10 and, via its ability to upregulate production of IL-10, inhibited expression of IL-2. These findings demonstrate that IL-12 differentially regulates expression of the Th1-type lymphokines, IFN-gamma and IL-2, in T lymphoblasts.
引用
收藏
页码:897 / 905
页数:9
相关论文
共 58 条
[1]   COOPERATION OF NATURAL-KILLER-CELL STIMULATORY FACTOR INTERLEUKIN-12 WITH OTHER STIMULI IN THE INDUCTION OF CYTOKINES AND CYTOTOXIC CELL-ASSOCIATED MOLECULES IN HUMAN T-CELLS AND NK-CELLS [J].
ASTEAMEZAGA, M ;
DANDREA, A ;
KUBIN, M ;
TRINCHIERI, G .
CELLULAR IMMUNOLOGY, 1994, 156 (02) :480-492
[2]   INTERLEUKIN-12 (IL-12) INDUCES TYROSINE PHOSPHORYLATION OF JAK2 AND TYK2 - DIFFERENTIAL USE OF JANUS FAMILY TYROSINE KINASES BY IL-2 AND IL-12 [J].
BACON, CM ;
MCVICAR, DW ;
ORTALDO, JR ;
REES, RC ;
O'SHEA, JJ ;
JOHNSTON, JA .
JOURNAL OF EXPERIMENTAL MEDICINE, 1995, 181 (01) :399-404
[3]   INTERLEUKIN-12 INDUCES TYROSINE PHOSPHORYLATION AND ACTIVATION OF STAT4 IN HUMAN-LYMPHOCYTES [J].
BACON, CM ;
PETRICOIN, EF ;
ORTALDO, JR ;
REES, RC ;
LARNER, AC ;
JOHNSTON, JA ;
O'SHEA, JJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (16) :7307-7311
[4]   INDUCTION OF INTERFERON-GAMMA PRODUCTION BY NATURAL-KILLER-CELL STIMULATORY FACTOR - CHARACTERIZATION OF THE RESPONDER CELLS AND SYNERGY WITH OTHER INDUCERS [J].
CHAN, SH ;
PERUSSIA, B ;
GUPTA, JW ;
KOBAYASHI, M ;
POSPISIL, M ;
YOUNG, HW ;
WOLF, SF ;
YOUNG, D ;
CLARK, SC ;
TRINCHIERI, G .
JOURNAL OF EXPERIMENTAL MEDICINE, 1991, 173 (04) :869-879
[5]  
CHIZZONITE R, 1992, J IMMUNOL, V148, P3117
[6]   SINGLE-STEP METHOD OF RNA ISOLATION BY ACID GUANIDINIUM THIOCYANATE PHENOL CHLOROFORM EXTRACTION [J].
CHOMCZYNSKI, P ;
SACCHI, N .
ANALYTICAL BIOCHEMISTRY, 1987, 162 (01) :156-159
[7]  
CHUA AO, 1994, J IMMUNOL, V153, P128
[8]   HUMAN T-CELL GROWTH-FACTOR - PARTIAL AMINO-ACID-SEQUENCE, CDNA CLONING, AND ORGANIZATION AND EXPRESSION IN NORMAL AND LEUKEMIC-CELLS [J].
CLARK, SC ;
ARYA, SK ;
WONGSTAAL, F ;
MATSUMOTOKOBAYASHI, M ;
KAY, RM ;
KAUFMAN, RJ ;
BROWN, EL ;
SHOEMAKER, C ;
COPELAND, T ;
OROSZLAN, S ;
SMITH, K ;
SARNGADHARAN, MG ;
LINDNER, SG ;
GALLO, RC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1984, 81 (08) :2543-2547
[9]   INTERLEUKIN-10 (IL-10) INHIBITS HUMAN LYMPHOCYTE INTERFERON GAMMA-PRODUCTION BY SUPPRESSING NATURAL-KILLER-CELL STIMULATORY FACTOR/IL-12 SYNTHESIS IN ACCESSORY CELLS [J].
DANDREA, A ;
ASTEAMEZAGA, M ;
VALIANTE, NM ;
MA, XJ ;
KUBIN, M ;
TRINCHIERI, G .
JOURNAL OF EXPERIMENTAL MEDICINE, 1993, 178 (03) :1041-1048
[10]  
DELPRETE G, 1993, J IMMUNOL, V150, P353