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

Research output: Contribution to journalArticle

51 Citations (Scopus)

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

Fingerprint

Peroxisome Proliferator-Activated Receptors
Myeloid Cells
Immunosuppression
Carcinogenesis
Inflammation
T-cells
Lymphokines
Doxycycline
T-Lymphocytes
Anti-Inflammatory Agents
Granulocyte Precursor Cells
Molecules
Interleukin-1
Sarcoma
Liver
Population
Monocytes
Interleukin-6
Blood
Up-Regulation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Inhibition of PPARγ in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis. / Wu, Lingyan; Yan, Cong; Czader, Magdalena; Foreman, Oded; Blum, Janice; Kapur, Reuben; Du, Hong.

In: Blood, Vol. 119, No. 1, 05.01.2012, p. 115-126.

Research output: Contribution to journalArticle

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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.",
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AU - Kapur, Reuben

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N2 - 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.

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