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MicroRNA-21 limits in vivo immune response-mediated activation of the IL-12/IFN-gamma pathway, Th1 polarization, and the severity of delayed-type hypersensitivity.

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.

Pubmed ID: 21849676

Authors

  • Lu TX
  • Hartner J
  • Lim EJ
  • Fabry V
  • Mingler MK
  • Cole ET
  • Orkin SH
  • Aronow BJ
  • Rothenberg ME

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Data

September 15, 2011

Associated Grants

  • Agency: NHLBI NIH HHS, Id: F30 HL104892-03
  • Agency: NHLBI NIH HHS, Id: F30HL104892
  • Agency: NIDDK NIH HHS, Id: P30 DK049216
  • Agency: NIDDK NIH HHS, Id: P30 DK049216-16
  • Agency: NIDDK NIH HHS, Id: P30DK049216
  • Agency: NIAID NIH HHS, Id: R01 AI083450
  • Agency: NIAID NIH HHS, Id: R01 AI083450-04
  • Agency: NIAID NIH HHS, Id: R01AI083450
  • Agency: NICHD NIH HHS, Id: T32 HD046387
  • Agency: NICHD NIH HHS, Id: T32 HD046387-05
  • Agency: NICHD NIH HHS, Id: T32HD046387
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Asthma
  • Blotting, Northern
  • Cell Differentiation
  • Cytokines
  • Disease Models, Animal
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Hypersensitivity, Delayed
  • Interferon-gamma
  • Interleukin-12
  • Mice
  • Mice, Knockout
  • MicroRNAs
  • Oligonucleotide Array Sequence Analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Th1 Cells