TY - JOUR
T1 - Modulation of TNF-α gene expression by IFN-γ and pamidronate in murine macrophages
T2 - Regulation by STAT1-dependent pathways
AU - Takagi, Kae
AU - Takagi, Masatoshi
AU - Kanangat, Siva
AU - Warrington, Kenneth J.
AU - Shigemitsu, Hidenobu
AU - Postlethwaite, Arnold E.
PY - 2005/2/15
Y1 - 2005/2/15
N2 - 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 Vγ2Vδ2 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-α production. Furthermore, pretreatment of murine macrophages with pamidronate before stimulation with IFN-γ significantly augments IFN-γ-dependent production of TNF-α. This pamidronate-mediated augmentation of TNF-α production results in sustained phosphorylation of the tyrosine residue at position 701 of STAT1 after IFN-γ treatment. Our data suggest that this sustained phosphorylation results from inhibition of protein tyrosine phosphatase activity. We also show that pamidronate treatment increases TNF-α production in vivo in mice. Pamidronate-augmented TNF-α production by macrophages might be a useful strategy for cytokine-based anticancer therapy.
AB - 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 Vγ2Vδ2 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-α production. Furthermore, pretreatment of murine macrophages with pamidronate before stimulation with IFN-γ significantly augments IFN-γ-dependent production of TNF-α. This pamidronate-mediated augmentation of TNF-α production results in sustained phosphorylation of the tyrosine residue at position 701 of STAT1 after IFN-γ treatment. Our data suggest that this sustained phosphorylation results from inhibition of protein tyrosine phosphatase activity. We also show that pamidronate treatment increases TNF-α production in vivo in mice. Pamidronate-augmented TNF-α production by macrophages might be a useful strategy for cytokine-based anticancer therapy.
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U2 - 10.4049/jimmunol.174.4.1801
DO - 10.4049/jimmunol.174.4.1801
M3 - Article
C2 - 15699106
AN - SCOPUS:13544258086
SN - 0022-1767
VL - 174
SP - 1801
EP - 1810
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -