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A cell permeable peptide inhibitor of NFAT inhibits macrophage cytokine expression and ameliorates experimental colitis

Elloumi, HZ and Maharshak, N and Rao, KN and Kobayashi, T and Ryu, HS and Mühlbauer, M and Li, F and Jobin, C and Plevy, SE (2012) A cell permeable peptide inhibitor of NFAT inhibits macrophage cytokine expression and ameliorates experimental colitis. PLoS ONE, 7 (3).

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Abstract

Nuclear factor of activated T cells (NFAT) plays a critical role in the development and function of immune and non-immune cells. Although NFAT is a central transcriptional regulator of T cell cytokines, its role in macrophage specific gene expression is less defined. Previous work from our group demonstrated that NFAT regulates Il12b gene expression in macrophages. Here, we further investigate NFAT function in murine macrophages and determined the effects of a cell permeable NFAT inhibitor peptide 11R-VIVIT on experimental colitis in mice. Treatment of bone marrow derived macrophages (BMDMs) with tacrolimus or 11R-VIVIT significantly inhibited LPS and LPS plus IFN-γ induced IL-12 p40 mRNA and protein expression. IL-12 p70 and IL-23 secretion were also decreased. NFAT nuclear translocation and binding to the IL-12 p40 promoter was reduced by NFAT inhibition. Experiments in BMDMs from IL-10 deficient (Il10 -/-) mice demonstrate that inhibition of IL-12 expression by 11R-VIVIT was independent of IL-10 expression. To test its therapeutic potential, 11R-VIVIT was administered systemically to Il10 -/- mice with piroxicam-induced colitis. 11R-VIVIT treated mice demonstrated significant improvement in colitis compared to mice treated with an inactive peptide. Moreover, decreased spontaneous secretion of IL-12 p40 and TNF in supernatants from colon explant cultures was demonstrated. In summary, NFAT, widely recognized for its role in T cell biology, also regulates important innate inflammatory pathways in macrophages. Selective blocking of NFAT via a cell permeable inhibitory peptide is a promising therapeutic strategy for the treatment of inflammatory bowel diseases. © 2012 Elloumi et al.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Elloumi, HZ
Maharshak, N
Rao, KN
Kobayashi, T
Ryu, HS
Mühlbauer, M
Li, F
Jobin, C
Plevy, SE
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorCombs, ColinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 27 March 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0034172
Schools and Programs: School of Medicine > Immunology
Refereed: Yes
Other ID: NLM PMC3313977
PubMed Central ID: PMC3313977
PubMed ID: 22479554
Date Deposited: 13 Sep 2012 20:14
Last Modified: 19 Jun 2021 10:55
URI: http://d-scholarship.pitt.edu/id/eprint/14160

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