title: 1,25-Dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level.
abstract: 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] inhibits lymphocyte proliferation and production of antibodies and lymphokines such as interleukin (IL)-2 and interferon gamma. These lymphocyte functions are dependent upon cytokines, including IL-1 alpha, IL-1 beta, IL-6 and tumour necrosis factor alpha (TNF-alpha), produced by the antigen presenting cells. In the present study we examined the effect of 1,25-(OH)2D3 on the production of these cytokines, as well as superoxide generation by freshly isolated mononuclear cells and partially purified monocytes. The immediate precursor of 1,25(OH)2D3, 25-OH D3, and the synthetic analogue MC 903 ('Calcipotriol') were examined in parallel. 1,25-(OH)2D3 dose-dependently inhibited the production of IL-alpha, IL-6 and TNF-alpha by Escherichia coli lipopolysaccharide (LPS)-stimulated monocytes, without affecting superoxide production. MC 903 had comparable effects while 25-OH D3 was ineffective. The inhibition caused by 1,25-(OH)2D3 was not abolished by supraoptimal concentrations of LPS or indomethacin. 1,25-(OH)2D3 had similar effects on secreted and cell-associated IL-alpha. Nuclear run-off analysis indicated that inhibition of these cytokines was not caused by impaired production of mRNA. Taken together, the study demonstrates a vitamin D-induced inhibitory effect of LPS-driven monokine production, which is most likely a vitamin D-receptor mediated phenomenon exerted at a post-transcriptional, presecretory level. Impaired monokine production may be of importance in 1,25-(OH)2D3-mediated inhibition of lymphocyte functions in vitro.
authors.affiliation: Laboratory of Medical Immunology, Rigshospitalet University Hospital, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Müller
authors.forename: P M
authors.initials: PM
authors.lastname: Haahr
authors.forename: M
authors.initials: M
authors.lastname: Diamant
authors.forename: K
authors.initials: K
authors.lastname: Rieneck
authors.forename: A
authors.initials: A
authors.lastname: Kharazmi
authors.forename: K
authors.initials: K
authors.lastname: Bendtzen
mesh_terms: D002112:Calcifediol / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C055085:calcipotriene; D002117:Calcitriol; D002112:Calcifediol