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Modulation of TNF- Gene Expression by IFN- and Pamidronate in Murine Macrophages: Regulation by STAT1-Dependent Pathways¹

Kae Takagi, Masatoshi Takagi, Siva Kanangat^*,, Kenneth J. Warrington, Hidenobu Shigemitsu^*, and Arnold E. Postlethwaite^2,*,

^* Department of Veterans Affairs Medical Center, Memphis, TN 38104; Divisions of Connective Tissue Diseases and Pulmonary Medicine, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163; and Department of Hematology/Oncology, St. Jude Children’s Research Hospital, Memphis, TN 38105

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 V2V2 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- production. Furthermore, pretreatment of murine macrophages with pamidronate before stimulation with IFN- significantly augments IFN--dependent production of TNF-. This pamidronate-mediated augmentation of TNF- production results in sustained phosphorylation of the tyrosine residue at position 701 of STAT1 after IFN- treatment. Our data suggest that this sustained phosphorylation results from inhibition of protein tyrosine phosphatase activity. We also show that pamidronate treatment increases TNF- production in vivo in mice. Pamidronate-augmented TNF- production by macrophages might be a useful strategy for cytokine-based anticancer therapy.

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