Modulation of TNF-alpha gene expression by IFN-gamma and pamidronate in murine macrophages: regulation by STAT1-dependent pathways.
Aminobisphosphonates are drugs used in the treatment of hypercalcemia, Paget's disease, osteoporosis, and malignancy. Some patients treated with aminobisphosphonates have a transient febrile reaction that may be caused by an increased serum concentration of proinflammatory cytokines. Aminobisphosphonates induce the production of certain proinflammatory cytokines in vitro, especially in cells of monocytic lineage. A unique feature of aminobisphosphonates is that they bind the Vgamma2Vdelta2 class of T cells, which are found only in primates, and stimulate cytokine production. The effects of aminobisphosphonates on other cells, including macrophages, are incompletely understood. We show in this study that treatment of murine macrophages with pamidronate, a second generation aminobisphosphonate, induces TNF-alpha production. Furthermore, pretreatment of murine macrophages with pamidronate before stimulation with IFN-gamma significantly augments IFN-gamma-dependent production of TNF-alpha. This pamidronate-mediated augmentation of TNF-alpha production results in sustained phosphorylation of the tyrosine residue at position 701 of STAT1 after IFN-gamma treatment. Our data suggest that this sustained phosphorylation results from inhibition of protein tyrosine phosphatase activity. We also show that pamidronate treatment increases TNF-alpha production in vivo in mice. Pamidronate-augmented TNF-alpha production by macrophages might be a useful strategy for cytokine-based anticancer therapy.
Takagi
Kae
K
Divisions of Connective Tissue Diseases and Pulmonary Medicine, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Takagi
Masatoshi
M
Kanangat
Siva
S
Warrington
Kenneth J
KJ
Shigemitsu
Hidenobu
H
Postlethwaite
Arnold E
AE
D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology*; D017930:Genes, Reporter; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000502:physiology; D047468:Immunoprecipitation; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000077268:Pamidronate; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
D002843:Chromatin; D004268:DNA-Binding Proteins; D004164:Diphosphonates; D007155:Immunologic Factors; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases; D000077268:Pamidronate