| First Author | Wu L | Year | 2012 |
| Journal | Blood | Volume | 119 |
| Issue | 1 | Pages | 115-26 |
| PubMed ID | 22053106 | Mgi Jnum | J:181660 |
| Mgi Id | MGI:5312196 | Doi | 10.1182/blood-2011-06-363093 |
| Citation | Wu L, et al. (2012) Inhibition of PPARgamma in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis. Blood 119(1):115-26 |
| abstractText | Peroxisome proliferator-activated receptor-gamma (PPARgamma) is an anti-inflammatory molecule. To study its biologic function in myeloid cells, dominant-negative PPARgamma (dnPPARgamma) was overexpressed in a myeloid-specific bitransgenic mouse model. In this bitransgenic system, overexpression of the dnPPARgamma-Flag fusion protein in myeloid-lineage cells abnormally elevated frequencies and total numbers of IL-7Ralpha(-)Lin(-)c-Kit(+)Sca-1(-), Lin(-)/Scal(+)/c-Kit(+), common myeloid, and granulocyte-monocyte progenitor populations in the BM. dnPPARgamma overexpression led to up-regulation of IL-1beta, IL-6, and TNFalpha in the blood plasma. As a result, CD11b(+)Ly6G(+) cells were systemically increased in association with activation of Stat3, NF-kappaB, 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 PPARgamma in myeloid-lineage cells plays a key role in controlling pro-inflammatory cytokine synthesis, MDSC expansion, immunosuppression, and the development of cancer. |
