Inhibition of PPARγ in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Peroxisome proliferator-activated receptor-γ(PPARγ) is an anti-inflammatory molecule. To study its biologic function in myeloid cells, dominant-negative PPARγ (dnPPARγ) was overexpressed in a myeloid-specific bitransgenic mouse model. In this bitransgenic system, overexpression of the dnPPARγ-Flag fusion protein in myeloidlineage cells abnormally elevated frequencies and total numbers of IL-7Rα -Lin -c- Kit +Sca-1 -, Lin -/Scal +/c-Kit +, common myeloid, and granulocyte-monocyte progenitor populations in the BM. dnPPARγ overexpression led to up-regulation of IL- 1β, IL-6, and TNFα in the blood plasma.As a result, CD11b +Ly6G + cells were systemically increased in association with activation of Stat3, NF-κB, Erk1/2, and p38 molecules. Myeloid-derived suppressor cells (MDSCs) inhibited the proliferation and lymphokine production of wild-typeCD4 + T cells in vitro. CD4 + T cells from doxycyclinetreated bitransgenic mice displayed reduced proliferation and lymphokine release. Both CD4 + and CD8 + T-cell populations were decreased in doxycycline-treated bitransgenic mice. Multiple forms of carcinoma and sarcoma in the lung, liver, spleen, and lymph nodes were observed in doxycycline- treated bitransgenic mice. BM transplantation revealed that a myeloid-autonomous defect was responsible for MDSC expansion, immunosuppression, and tumorigenesis in these mice. These studies suggest that anti-inflammatory PPARγ in myeloid-lineage cells plays a key role in controlling pro-inflammatory cytokine synthesis, MDSC expansion, immunosuppression, and the development of cancer.

Original languageEnglish (US)
Pages (from-to)115-126
Number of pages12
JournalBlood
Volume119
Issue number1
DOIs
StatePublished - Jan 5 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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