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25-Hydroxyvitamin D₃ Metabolism by Lipopolysaccharide-Stimulated Normal Human Macrophages^*

HELMUT REICHEL, H. PHILLIP KOEFFLER, JUNE E. BISHOP and ANTHONY W. NORMAN

Division of Biomedical Sciences and the Department of Biochemistry, University of California Riverside, California 92521
The Division of Hematology, the Department of Medicine, University of California Los Angeles, California 90024

Address all correspondence and requests for reprints to: Prof. Anthony W. Norman, Department of Biochemistry, University of California, Riverside, California 92521.

Cultured normal human pulmonary alveolar macrophages and peripheral blood monocyte-derived macro-phages were studied for their capacity to metabolize [³H]25-hydroxyvitamin D₃ (25OHD₃). Incubation of macrophages with bacterial lipopolysaccharide (LPS) resulted in the conversion of [³H]25OHD₃ to a more polar vitamin D₃ metabolite (up to 15 pmol/106 cells). Untreated macrophages did not synthesize this metabolite. Several findings suggested that the metabolite was the biologically active form of vitamin D₃, namel y 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃]. (1) The metabolite comigrated with chemically synthesized 1,25-(OH)₂D₃ on four different high performance liquid chromatographic systems. (2) The metabolite had the same affinity for the chick intestinal 1,25-(OH)₂D₃ receptor as authentic 1,25-(OH)₂D₃. (3) The biological activity of the macrophage metabolite in vivo (stimulation of intestinal calcium absorption and bone calcium mobilization in rachitic chicks) was identical to the activity of chemically synthesized 1,25-(OH)₂D₃. The LPS-stimulated synthesis of the 1,25-(OH)₂D₃-like compound by macrophages was dose dependent in a linear fashion; a half-maximal response was typically found with 100–200 ng LPS/10⁶ cells. Polymyxin B abolished the effects of LPS on 25OHD₃ metabolism in macrophages. Our data suggest that LPS-stimulated macrophages can modulate, on a local level, the function of l,25-(OH)₂D₃-responsive cells by releasing the l,25-(OH)₂D₃-like metabolite.

^* This work was supported by USPHS Grants CA-26038, CA-33936, and AM-14750.

Supported by the Deutsche Forschungs gemeinschaft (Re 613/1-1).

Supported by a Career Development Award, the Murray Geisler Memorial Foundation, and the Louis Fagin Leukemia Research Foundation and is a member of the Jonsson Cancer Center.

Received March 10, 1986.

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