Altered IL-4 mRNA stability correlates with Th1 and Th2 bias and susceptibility to hypersensitivity pneumonitis in two inbred strains of mice.
Previously, we have shown in a model of hypersensitivity pneumonitis that Th1-biased C57BL/6 mice are susceptible and Th2-biased DBA/2 mice are resistant to disease. We also showed that this was explained in part by differential regulation of IL-12 by IL-4. For these reasons, we postulated that C57BL/6 and DBA/2 mice differentially express IL-4. In this study, we show that C57BL/6 immune cells express Th2 but not Th1 cytokines at lower levels than DBA/2 cells. We also found that C57BL/6 splenocytes exhibit decreased mRNA stability of Th2 cytokines, relative to DBA/2 splenocytes. Stability of IL-2 and IFN-gamma were similar in the two strains of mice. Differences in Th2 cytokine mRNA stability between C57BL/6 and DBA/2 cells were not due to sequence polymorphism at specific regions of the IL-4/IL-13 locus. Furthermore, expression of Th1- and Th2-specific transcription factors T-bet and GATA-3, as well as the nuclear factor of activated T cells transcription factor, NFATc, was not significantly different between the two mice. Our data suggest that decreased mRNA stability of Th2 cytokines in C57BL/6 splenocytes may underlie the differential susceptibility to hypersensitivity pneumonitis between C57BL/6 and DBA/2 mice. Moreover, our results indicate that regulation of mRNA stability may serve as an important mechanism underlying Th1/Th2 immune polarization.
Butler
Noah S
NS
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Iowa College of Medicine and Veterans Administration Medical Center, Iowa City, IA 52242, USA. noah-butler@uiowa.edu
Monick
Martha M
MM
Yarovinsky
Timur O
TO
Powers
Linda S
LS
Hunninghake
Gary W
GW
D000542:Alveolitis, Extrinsic Allergic / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D050990:GATA3 Transcription Factor; D005819:Genetic Markers / Q000276:immunology; D016130:Immunophenotyping; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011110:Polymorphism, Genetic / Q000276:immunology; D020871:RNA Stability / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D005819:Genetic Markers; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D015847:Interleukin-4