Sensitivity and Resistance to Regulation by IL-4 in Th17 Cells: MolecularMechanisms and Significance in Autoimmune Disease.

Th17;Arthritis;Cytokine;IL-4;IL-17;Microbiology and Immunology;Pathology;Health Sciences;Immunology

Cooney, Laura A.Lukacs, Nicholas W. ;

University of Michigan

关键词: Th17;    Arthritis;    Cytokine;    IL-4;    IL-17;    Microbiology and Immunology;    Pathology;    Health Sciences;    Immunology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/77923/ltesmer_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Th17 cells promote immune-mediated diseases, including rheumatoid arthritis, and a thorough understanding of Th17 responses may prove therapeutically useful. We therefore chose to characterize the mechanisms of Th17 suppression by the Th2 cytokine IL-4.After one week of in vitro differentiation or a two week immunization in vivo, IL-4 inhibits expression of several Th17-family genes, including IL-17A, IL-17F and RORγt, and this suppression overcomes stimulation by TGFβ, IL-6 and IL-23. However, suppression by IL-4 is unstable and does not induce Th2 conversion. The mechanism of suppression downstream of the IL-4R is dependent on STAT6 but independent of STAT5, IRS-2 and GATA-3. At the chromatin level, IL-4 up-regulates markers of active transcription at the Il17a locus, including histone acetylation and PolII binding, despite clear down-regulation of IL-17A message. However, IL-4 also displaces the transcriptional inducer STAT3 from the Il17a promoter, suggesting that a transcriptional repressor may take its place.We found that Th17 cells undergo a process of maturation, whereby in vitro-generated Th17 cells stimulated for three weeks or in vivo-generated Th17 cells re-stimulated for three days become resistant to suppression by IL-4. This transition depends on a combination of TCR and cytokine stimuli and results in desensitization of the IL-4R. Specifically, mature Th17 cells lose the ability to phosphorylate STAT6 in response to IL-4, despite normal expression of the IL-4R. The suppression of IL-4R signaling did not depend on SOCS5, but may be mediated by SOCS1.To explore the regulation of IL-17 by IL-4 and IFNγ in collagen-induced arthritis (CIA), we treated mice with cytokine-neutralizing antibodies in vivo during disease. The results showed that IFNγ plays a protective role via down-regulation of IL-17. IL-4, once released from suppression by IFNγ, also plays a protective role, particularly in bone and cartilage erosion. However, the protective role of IL-4 is not mediated by suppression of IL-17. Interestingly, when both IFNγ and IL-4 are neutralized, mice develop severe arthritis independent of IL-17.These results indicate that regulation of Th17-driven tissue inflammation is possible. However, effective use of such approaches depends on detailed understanding of Th17 differentiation and maturation in a specific autoimmune disease.