IMMUNOBIOLOGY Inhibition of PPAR in myeloid-lineage cells induces systemic inflammation,

(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 bitrans-genic system, overexpression of the dnPPAR-Flag fusion protein in myeloid-lineage cells abnormally elevated frequen-cies and total numbers of IL-7RLinc-KitSca-1, Lin/Scal/c-Kit, common myeloid, and granulocyte-monocyte pro-genitor populations in the BM. dnPPAR overexpression led to up-regulation of IL-1, IL-6, and TNF in the blood plasma. As a result, CD11bLy6G cells were systemi-cally increased in association with activa-tion of Stat3, NF-B, Erk1/2, and p38 mol-ecules. Myeloid-derived suppressor cells (MDSCs) inhibited the proliferation and lym-phokineproductionofwild-typeCD4T cells in vitro. CD4 T cells from doxycycline-treated bitransgenic mice displayed re-duced proliferation and lymphokine release. Both CD4 and CD8 T-cell populations were decreased in doxycycline-treated bi-transgenic mice. Multiple forms of carci-noma and sarcoma in the lung, liver, spleen, and lymph nodes were observed in doxycy-cline-treated bitransgenic mice. BM trans-plantation revealed that a myeloid-autono-mous defect was responsible for MDSC expansion, immunosuppression, and tu-morigenesis in these mice. These studies suggest that anti-inflammatory PPAR in myeloid-lineage cells plays a key role in controlling pro-inflammatory cytokine syn-thesis, MDSC expansion, immunosuppres-sion, and the development of cancer. (Blood. 2012;119(1):115-126