Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair

被引:204
作者
Sandler, NG
Mentink-Kane, MM
Cheever, AW
Wynn, TA
机构
[1] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA
[2] Biomed Res Inst, Rockville, MD 20852 USA
关键词
D O I
10.4049/jimmunol.171.7.3655
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
T helper 1 responses are typically proinflammatory, while Th2 responses have been considered regulatory. Interestingly, Th2 responses characterize a number of pulmonary diseases, many of which terminate in tissue remodeling and fibrosis. We developed a mouse model using Schistosoma mansoni eggs and cytokine-deficient mice to induce highly polarized Th1- or Th2-type inflammation in the lung. In this study, we examined the pathology and cytokine profiles in Th1- and Th2-polarized environments and used oligonucleotide microarray analysis to decipher the genes responsible for these effects. We further elaborated on the results using IL-10- and IL-13-deficient mice because these cytokines are believed to be the central regulators of Th2-associated pathology. We found that the Th1-polarized mice developed small granulomas with less fibrosis while expressing genes characteristic of tissue damage. Th2-polarized mice, in contrast, formed large granulomas with massive collagen deposition and up-regulated genes associated-with wound healing, specifically, arginase, collagens, matrix metalloproteinases (MMPs), and tissue inhibitors of MMP. In addition, several members of the chitinase-like family were up-regulated in the lung following egg challenge. We also developed a method of defining the net collagen deposition using the expression profiles of several collagen, MMP, and tissue inhibitors of MMP genes. We found that Th1-polarized mice did not elaborate collagens or MMPs and therefore did not have a significant capacity for repair in this model. Thus, Th1-mediated inflammation is characterized by tissue damage, while Th2 directs wound healing and fibrosis.
引用
收藏
页码:3655 / 3667
页数:13
相关论文
共 98 条
[1]   Functional diversity of helper T lymphocytes [J].
Abbas, AK ;
Murphy, KM ;
Sher, A .
NATURE, 1996, 383 (6603) :787-793
[2]   INVITRO FORMATION OF HYBRID FIBRILS OF TYPE-V COLLAGEN AND TYPE-I COLLAGEN - LIMITED GROWTH OF TYPE-I COLLAGEN INTO THICK FIBRILS BY TYPE-V COLLAGEN [J].
ADACHI, E ;
HAYASHI, T .
CONNECTIVE TISSUE RESEARCH, 1986, 14 (04) :257-266
[3]   Growth factor and cytokine modulation of trabecular meshwork matrix metalloproteinase and TIMP expression [J].
Alexander, JP ;
Samples, JR ;
Acott, TS .
CURRENT EYE RESEARCH, 1998, 17 (03) :276-285
[4]  
[Anonymous], 2000, AM J RESP CRIT CARE, V161, P646, DOI DOI 10.1164/AJRCCM.161.2.ATS3-00
[5]   Molecular cloning of four novel murine ribonuclease genes: unusual expansion within the Ribonuclease A gene family [J].
Batten, D ;
Dyer, KD ;
Domachowske, JB ;
Rosenberg, HF .
NUCLEIC ACIDS RESEARCH, 1997, 25 (21) :4235-4239
[6]   Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver [J].
Benyon, RC ;
Iredale, JP ;
Goddard, S ;
Winwood, PJ ;
Arthur, MJP .
GASTROENTEROLOGY, 1996, 110 (03) :821-831
[7]   Gelatinase B is required for alveolar bronchiolization after intratracheal bleomycin [J].
Betsuyaku, T ;
Fukuda, Y ;
Parks, WC ;
Shipley, JM ;
Senior, RM .
AMERICAN JOURNAL OF PATHOLOGY, 2000, 157 (02) :525-535
[8]   Identification of a novel acidic mammalian chitinase distinct from chitotriosidase [J].
Boot, RG ;
Blommaart, EFC ;
Swart, E ;
Ghauharali-van der Vlugt, K ;
Bijl, N ;
Moe, C ;
Place, A ;
Aerts, JMFG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (09) :6770-6778
[9]  
Cai GP, 1997, J CELL BIOCHEM, V67, P257, DOI 10.1002/(SICI)1097-4644(19971101)67:2<257::AID-JCB11>3.0.CO
[10]  
2-C