The cDNA encoding IL-11 was isolated from a primate bone marrow stromal cell line through mammalian cell expression cloning method based on its ability to stimulate the proliferation of an IL-6-dependent mouse plasmacytoma cell line, T1165. Like most of the cytokines, IL-11 exerts various biological activities through the interactions-between the ligand and the receptors present on the target cells. IL-11 has been shown to be able to synergize with IL-3 in supporting human and murine megakaryocyte colony formation, stimulate the T-cell dependent development of immunoglobulin-producing B cells and act synergistically with IL-3 to shorten the Go period of early hematopoietic progenitors. Recent studies have shown that IL-11 can also induce the synthesis of acute-phase proteins and inhibits the process of adipocyte differentiation. The fact that an adipocyte cell line, 3T3-Ll, can respond to a stromal fibroblast-derived growth factor like IL-11, may .provide a useful system to study the cell-cell interactions in the hematopoietic microenvironment. The long term objective of this proposal is to understand the role of IL-11 in regulating hematopoiesis at the molecular and cellular level. Since most of the biological activities of IL-11 overlaps with those of IL-6, we hypothesize that these two cytokines may utilize similar signal transduction pathways or may even share common receptors. The proposed work aims to (1) molecularly clone the IL-11 receptor: this will be achieved by (i) cloning the receptor based on the functional interaction between the i ligand and the receptor by screening a 3T3-Ll cDNA expression library based on the ability of the IL-11 receptor cDNA expressing IL-3-dependent FDCP-1 cells to grow in the presence of IL-11 and in the absence of IL-3; (ii) cloning the receptor based on the ligand binding by screening a 3T3-Ll cDNA expression library using microscopic emulsion autoradiography with radioiodinated IL-11 and (2) study IL-11-mediated signal transduction pathways in comparison with those of IL-6: this will be accomplished by (i) analyzing the significance of protein tyrosine phosphorylation, G protein, protein kinase C and adenyl cyclase in IL11-mediated sinal transduction pathways; (ii) identifying phospholipid-derived second messengers involved in the IL-11-mediated signaling; (iii) examining the primary response genes activated by IL-11-mediated signal transduction. The accomplishment of this proposal will not only help us better understand the biological relevance of IL-11 and cell-cell interactions in the normal hematopoietic microenvironment but also uncover some of the mechanisms involved in the IL-11-mediated signal transduction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL048819-03
Application #
2224906
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1992-08-01
Project End
1997-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Zheng, Gang; Ning, Jinying; Yang, Yu-Chung (2007) PLAGL2 controls the stability of Pirh2, an E3 ubiquitin ligase for p53. Biochem Biophys Res Commun 364:344-50
Chou, Yu-Ting; Yang, Yu-Chung (2006) Post-transcriptional control of Cited2 by transforming growth factor beta. Regulation via Smads and Cited2 coding region. J Biol Chem 281:18451-62
Zheng, Gang; Yang, Yu-Chung (2006) Acetylation and alternative splicing regulate ZNF76-mediated transcription. Biochem Biophys Res Commun 339:1069-75
Zheng, Gang; Yang, Yu-Chung (2005) Sumoylation and acetylation play opposite roles in the transactivation of PLAG1 and PLAGL2. J Biol Chem 280:40773-81
Zheng, Gang; Yang, Yu-Chung (2004) ZNF76, a novel transcriptional repressor targeting TATA-binding protein, is modulated by sumoylation. J Biol Chem 279:42410-21
Xiao, Hui; Chung, Jin; Kao, Hung-Ying et al. (2003) Tip60 is a co-repressor for STAT3. J Biol Chem 278:11197-204
Yin, Zhan; Haynie, Jennifer; Williams, Bryan R G et al. (2003) C114 is a novel IL-11-inducible nuclear double-stranded RNA-binding protein that inhibits protein kinase R. J Biol Chem 278:22838-45
Yin, Zhan; Haynie, Jennifer; Yang, Xiaoming et al. (2002) The essential role of Cited2, a negative regulator for HIF-1alpha, in heart development and neurulation. Proc Natl Acad Sci U S A 99:10488-93
Xiao, Hui; Yin, Tinggui; Wang, Xin-Yuan et al. (2002) Specificity of interleukin-2 receptor gamma chain superfamily cytokines is mediated by insulin receptor substrate-dependent pathway. J Biol Chem 277:8091-8
Sliva, D; Gu, M; Zhu, Y X et al. (2000) 14-3-3zeta interacts with the alpha-chain of human interleukin 9 receptor. Biochem J 345 Pt 3:741-7

Showing the most recent 10 out of 35 publications