Mechanism of IL-4-mediated up-regulation of the polymeric Ig receptor: Role of STAT6 in cell type-specific delayed transcriptional response

被引:49
作者
Schjerven, H [1 ]
Brandtzaeg, P [1 ]
Johansen, FE [1 ]
机构
[1] Univ Oslo, Inst Pathol, Lab Immunohistochem & Immunopathol, Rikshosp, N-0027 Oslo, Norway
关键词
D O I
10.4049/jimmunol.165.7.3898
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The polymeric IgR (pIgR) mediates transport of dimeric IgA and pentameric IgM across mucosal epithelia, thereby generating secretory Abs, Its expression is up-regulated at the transcriptional level by IL-4 in HT-29 cells. In this study, we demonstrate that IL-4 mediates up-regulation of human pIgR through a 554-bp IL-4-responsive enhancer in intron 1, Mutation of a binding site for STAT-6 within this region abolished IL-4-induced enhancement, while an adjacent putative C/EBP site was dispensable. IL-4 treatment induced binding of STAT6 to the intronic STAT6 site, but cooperation with nearby upstream and downstream DNA elements was required for IL-4 responsiveness. Furthermore, IL-4-mediated increased transcription of the pIgR-derived enhancer, like the endogenous pIgR gene, required de novo protein synthesis. Interestingly, a conditionally active form of STAT6 sufficed to activate a pIgR-derived enhancer in HT-29 cells, but not in Cos-1 cells, suggesting a requirement for cell type-specific factors. Thus, STAT6 activation mediates a delayed transcriptional enhancement of pIgR by induction of a de novo synthesized protein that cooperates with STAT6 itself bound to its cognate DNA element in intron 1, This mechanism may represent a general strategy for how pleiotropic cytokines elicit cell type-specific transcriptional responses.
引用
收藏
页码:3898 / 3906
页数:9
相关论文
共 52 条
[1]  
Ackermann LW, 1999, J IMMUNOL, V162, P5112
[2]   The B-cell system of human mucosae and exocrine glands [J].
Brandtzaeg, P ;
Farstad, IN ;
Johansen, FE ;
Morton, HC ;
Norderhaug, IN ;
Yamanaka, T .
IMMUNOLOGICAL REVIEWS, 1999, 171 :45-87
[3]   EPITHELIAL EXPRESSION OF HLA, SECRETORY COMPONENT (POLY-IG RECEPTOR), AND ADHESION MOLECULES IN THE HUMAN ALIMENTARY-TRACT [J].
BRANDTZAEG, P ;
HALSTENSEN, TS ;
HUITFELDT, HS ;
KRAJCI, P ;
KVALE, D ;
SCOTT, H ;
THRANE, PS .
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 1992, 664 :157-179
[4]   CHARACTERIZATION OF AN INTERLEUKIN-4 (IL-4) RESPONSIVE REGION IN THE IMMUNOGLOBULIN HEAVY-CHAIN GERMLINE EPSILON-PROMOTER - REGULATION BY NF-IL-4, A C/EBP FAMILY MEMBER AND NF-KAPPA-B-P50 [J].
DELPHIN, S ;
STAVNEZER, J .
JOURNAL OF EXPERIMENTAL MEDICINE, 1995, 181 (01) :181-192
[5]  
Denning GM, 1996, J IMMUNOL, V156, P4807
[6]   Isolation and genomic analysis of the rat polymeric immunoglobulin receptor gene terminal domain and transcriptional control region [J].
Fodor, E ;
Feren, A ;
Jones, A .
DNA AND CELL BIOLOGY, 1997, 16 (02) :215-225
[7]   Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4 [J].
Gupta, S ;
Jiang, M ;
Anthony, A ;
Pernis, AB .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 190 (12) :1837-1848
[8]   The first exon of the human sc gene contains an androgen responsive unit and an interferon regulatory factor element [J].
Haelens, A ;
Verrijdt, G ;
Schoenmakers, E ;
Alen, P ;
Peeters, B ;
Rombauts, W ;
Claessens, F .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 1999, 153 (1-2) :91-102
[9]  
Jahnsen FL, 1999, J IMMUNOL, V163, P1545
[10]   Absence of epithelial immunoglobulin A transport, with increased mucosal leakiness, in polymeric immunoglobulin receptor/secretory component-deficient mice [J].
Johansen, FE ;
Pekna, M ;
Norderhaug, IN ;
Haneberg, B ;
Hietala, MA ;
Krajci, P ;
Betsholtz, C ;
Brandtzaeg, P .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 190 (07) :915-921