Maqola

MicroRNA-21 Limits In Vivo Immune Response-Mediated Activation of the IL-12/IFN-γ Pathway, Th1 Polarization, and the Severity of Delayed-Type Hypersensitivity

Thomas X. LuDivision of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229Jochen C. HartnerDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital , Boston, MA 02115Eun‐Jin LimDivision of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229Victoria FabryDivision of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229Melissa K. MinglerDivision of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229Eric T. ColeDivision of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229Stuart H. OrkinDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Children’s Hospital , Boston, MA 02115Bruce J. AronowDivision of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229Marc E. RothenbergDivision of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229

2011en

ABI

Annotatsiya

An altered balance between Th1 and Th2 cytokines is responsible for a variety of immunoinflammatory disorders such as asthma, yet the role of posttranscriptional mechanisms, such as those mediated by microRNAs (miRs), in adjusting the relative magnitude and balance of Th cytokine expression have been largely unexplored. In this study, we show that miR-21 has a central role in setting a balance between Th1 and Th2 responses to Ags. Targeted ablation of miR-21 in mice led to reduced lung eosinophilia after allergen challenge, with a broadly reprogrammed immunoactivation transcriptome and significantly increased levels of the Th1 cytokine IFN-γ. Biological network-based transcriptome analysis of OVA-challenged miR-21(-/-) mice identified an unexpected prominent dysregulation of IL-12/IFN-γ pathways as the most significantly affected in the lungs, with a key role for miR-21 in IFN-γ signaling and T cell polarization, consistent with a functional miR-21 binding site in IL-12p35. In support of these hypotheses, miR-21 deficiency led dendritic cells to produce more IL-12 after LPS stimulation and OVA-challenged CD4(+) T lymphocytes to produce increased IFN-γ and decreased IL-4. Further, loss of miR-21 significantly enhanced the Th1-associated delayed-type hypersensitivity cutaneous responses. Thus, our results define miR-21 as a major regulator of Th1 versus Th2 responses, defining a new mechanism for regulating polarized immunoinflammatory responses.

Hali tarjima qilinmagan

Identifikatorlar

DOI: 10.4049/jimmunol.1101235

Iqtiboslar va manbalar

2 ta iqtibos0 ta foydalanilgan manba

Koʻrsatkichlar — AkademScholar