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Inhibition of PPAR? in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis.

ABSTRACT: Peroxisome proliferator-activated receptor-? (PPAR?) is an anti-inflammatory molecule. To study its biologic function in myeloid cells, dominant-negative PPAR? (dnPPAR?) was overexpressed in a myeloid-specific bitransgenic mouse model. In this bitransgenic system, overexpression of the dnPPAR?-Flag fusion protein in myeloid-lineage cells abnormally elevated frequencies and total numbers of IL-7R?(-)Lin(-)c-Kit(+)Sca-1(-), Lin(-)/Scal(+)/c-Kit(+), common myeloid, and granulocyte-monocyte progenitor populations in the BM. dnPPAR? overexpression led to up-regulation of IL-1?, IL-6, and TNF? in the blood plasma. As a result, CD11b(+)Ly6G(+) cells were systemically increased in association with activation of Stat3, NF-?B, Erk1/2, and p38 molecules. Myeloid-derived suppressor cells (MDSCs) inhibited the proliferation and lymphokine production of wild-type CD4+ T cells in vitro. CD4+ T cells from doxycycline-treated 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 PPAR? in myeloid-lineage cells plays a key role in controlling pro-inflammatory cytokine synthesis, MDSC expansion, immunosuppression, and the development of cancer.

SUBMITTER: Wu L

PROVIDER: S-EPMC3251224 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Wu Lingyan L Yan Cong C Czader Magdalena M Foreman Oded O Blum Janice S JS Kapur Reuben R Du Hong H

Blood 20111103 1

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 myeloid-lineage cells abnormally elevated frequencies and total numbers of IL-7Rα(-)Lin(-)c-Kit(+)Sca-1(-), Lin(-)/Scal(+)/c-Kit(+), common myeloid, and granulocyte-monocyte progenit ...[more]

PMID: 22053106

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Inhibition of PPAR? in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis.

Publications

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

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