Comparative effects of interferon-gamma and all- trans retinoic acid on secreted and surface-associated matrix metalloproteinase-9 expression of human monocytes.
Matrix metalloproteinase-9 is involved in inflammation and tumor progression. We previously demonstrated that interferon type I (alpha/beta) and II (gamma) inhibit matrix metalloproteinase-9 (92kDa) gene expression on lymphocytes from patients with B chronic lymphocytic leukemia and human monocytes. Since all-trans retinoic acid (ATRA) can regulate some interferon -responsive genes, we studied here the effects of all-trans retinoic acid onto matrix metalloproteinase-9 levels in these cells. By using RT-PCR, ELISA and zymography experiments, we showed that all-trans retinoic acid down-regulated matrix metalloproteinase-9 synthesis (mRNA,protein) and secretion. The inhibitory action of all-trans retinoic acid toward matrix metalloproteinase-9 was however not associated with the STAT1/IRF-1 pathway involved in interferon-mediated matrix metalloproteinase-9 inhibition indicating that all-trans retinoic acid did not bypass IFN receptor signaling. Using flow cytometry, we detected on the surface of monocytes low expression of matrix metalloproteinase-9 and Fc-gammaRI, and high expression of HLA-DR, beta1 and beta2 integrins. Enhancement of Fc-gammaRI and HLA-DR on monocytes by interferon-gamma, but not by all-trans retinoic acid, was accompanied by up-regulation of surface matrix metalloproteinase-9. Furthermore, we showed that all-trans retinoic acid down-regulated matrix metalloproteinase-9 expression in lymphocytes of untreated patients with early stage B chronic lymphocytic leukemia. Together, our data suggest the potential relevance of all-trans retinoic acid as a pharmacological tool to attenuate matrix metalloproteinase-9 secretion in pathological situations.
Nguyen
J
J
INSERM 507, Hôpital Necker Bâtiment Lavoisier 161 rue de Sèvres, 75015 Paris, France.
Dumont
J
J
Bauvois
B
B
D000954:Antigens, Surface / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000954:Antigens, Surface; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014409:Tumor Necrosis Factor-alpha; D014212:Tretinoin; D007371:Interferon-gamma; D020780:Matrix Metalloproteinase 9