1,25-Dihydroxyvitamin D3-mediated suppression of T lymphocyte functions and failure of T cell-activating cytokines to restore proliferation.
1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown to be a potent inhibitor of lymphocyte proliferation in vitro. The present study was undertaken to determine if this is caused by a direct effect on the lymphocytes, and to evaluate to what degree this suppression may be restored by the addition of cytokines. 1,25-(OH)2D3, > or = 10(-10) M, significantly inhibited the proliferation of pokeweed mitogen (PWM)-driven human peripheral blood mononuclear cells (MNC). Depletion of monocytes did not alter the response to 1,25-(OH)2D3. The antiproliferative effect was preceded by decreased production of interleukin (IL)-1 alpha and lymphotoxin (LT), both of which are crucially involved in T cell activation. However, the suppressive effect of 1,25-(OH)2D3, seen in MNC cultures stimulated with PWM alone, was of the same magnitude as the effect seen in MNC cultures stimulated with a combination of PWM and recombinant (r)IL-1 alpha, rIL-6, recombinant tumour necrosis factor (rTNF) alpha, rIL-2 or rLT, as well as PWM plus conditioned medium. Although pretreatment of monocytes for 2 h with 1,25-(OH)2D3 caused significant reduction in the release of IL-1 alpha and TNF alpha, reconstitution of monocyte-depleted cultures with similarly treated monocytes had no inhibitory effect on the proliferative response. In conclusion, even though it cannot be excluded that a low but critical number of monocytes are essential for the suppressive effect of 1,25-(OH)2D3-mediated inhibition of MNC proliferation, the inhibition is most likely the result of a direct effect on the lymphocytes and independent of monocytes and exogenously added cytokines.(ABSTRACT TRUNCATED AT 250 WORDS)
Müller
K
K
Medical Department TTA, Rigshospitalet University Hospital, Copenhagen, Denmark.
Rieneck
K
K
Hansen
M B
MB
Bendtzen
K
K
D000328:Adult; D002117:Calcitriol / Q000276:immunology*; D016207:Cytokines / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008233:Lymphotoxin-alpha / Q000096:biosynthesis; D011043:Pokeweed Mitogens; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000502:physiology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology
D016207:Cytokines; D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D008233:Lymphotoxin-alpha; D011043:Pokeweed Mitogens; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D002117:Calcitriol