title: Inhibition of PPARγ in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis.
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 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 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-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 PPARγ in myeloid-lineage cells plays a key role in controlling pro-inflammatory cytokine synthesis, MDSC expansion, immunosuppression, and the development of cancer.
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5188, USA.
authors: Lingyan
authors: L
authors: Wu
authors: Cong
authors: C
authors: Yan
authors: Magdalena
authors: M
authors: Czader
authors: Oded
authors: O
authors: Foreman
authors: Janice S
authors: JS
authors: Blum
authors: Reuben
authors: R
authors: Kapur
authors: Hong
authors: H
authors: Du
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005799:Genes, Dominant; D006412:Hematopoietic Stem Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012509:Sarcoma / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013160:Splenic Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015854:Up-Regulation
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D047495:PPAR gamma; D012333:RNA, Messenger; D020395:Receptors, Interleukin-7; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; C415350:interleukin-7 receptor, alpha chain; D019009:Proto-Oncogene Proteins c-kit