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J Biol Chem, Vol. 273, Issue 27, 16730-16738, July 3, 1998
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From the We demonstrate that adrenomedullin (AM) is
produced and secreted from cultured murine monocyte/macrophage cell
line (RAW 264.7) as well as mouse peritoneal macrophage. Immunoreactive
(IR) AM secreted from RAW 264.7 cells was chromatographically
identified to be native AM. To elucidate the regulation mechanism of AM
production in macrophage, we examined the effects of various substances
inducing differentiation or activation of monocyte/macrophage. Phorbol ester (TPA), retinoic acid (RA), lipopolysaccharide (LPS), and interferon- National Cardiovascular Center Research
Institute,
(IFN-) increased AM production 1.5-7-fold in RAW 264.7 cells in a dose- as well as time-dependent manner. By
LPS stimulation, the AM mRNA level in RAW 264.7 cells was augmented up to 7-fold after 14 h incubation. RA exerted a synergistic
effect when administered with TPA, LPS, or IFN-, whereas IFN-
completely suppressed AM production in RAW 264.7 cells stimulated with
LPS. Dexamethasone, hydrocortisone, estradiol, and transforming growth factor-
dose-dependently suppressed AM production in RAW
264.7 cells. AM production was also investigated in mouse peritoneal macrophage. Primary mouse macrophage secreted IR-AM at a rate similar
to that of RAW 264.7 cells, and its production was enhanced 9-fold by
LPS stimulation. AM was found to increase basal secretion of tumor
necrosis factor 
(TNF-) from RAW 264.7 cells, whereas AM
suppressed the secretion of TNF- and interleukin-6 from that stimulated with LPS. Thus, macrophage should be recognized as one of
the major sources of AM circulating in the blood. Especially in cases
of sepsis and inflammation, AM production in macrophage is augmented,
and the secreted AM is deduced to function as a modulator of cytokine
production.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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