Inhibition of Interleukin-1 Production by 1,25-Dihydroxyvitamin D₃

Abstract

The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], inhibits the proliferation of T lymphocytes and production of growth-promoting factors (including interleukin-2) (IL2) in CTLL2 murine cells. In this study, we investigated the role of monocytes in this hormone-mediated inhibitory effect, by testing the effects of 1,25-(OH)2D3 on the ability of the mitogenic lectin phytohemagglutinin (PHA) to induce T cell activation in either a monocyte-dependent or phorbol myristate acetate (PMA)-driven (monocyte-independent) system. The results indicate that proliferation of T cells and production of growth-promoting factors are inhibited by 1,25-(OH)2D3 only in the monocyte-dependent system. Preincubation of monocytes with 1,25-(OH)2D3 for various periods of time and subsequent removal of the hormone resulted in inhibition of the PHA-driven proliferation of T cells. Preincubation for 2 h resulted in 20% inhibition, while preincubation for 36 h reduced proliferation to 50% of the control value [no 1,25-(OH)2D3 exposure]. These data suggested that monocytes are important participants in 1,25-(OH)2D3-mediated events. Therefore, we tested the effects of the hormone on the production of IL1, a monocyte-derived product thought to be involved in the induction of IL2 release and the subsequent development of the T cell proliferative response. 1,25-(OH)2D3 inhibited the production of both extracellular and cell-associated immunoreactive IL1 alpha and IL1 beta. Indomethacin, a prostaglandin synthetase inhibitor, did not alter the inhibitory properties of 1,25-(OH)2D3, suggesting that prostaglandins are not responsible for the inhibitory phenomenon. We conclude that part of the ability of 1,25-(OH)2D3 to inhibit T cell proliferation may be due to direct effects on monocytes by down-regulating IL-1 production. However, it is unlikely that the immunoregulatory properties of 1,25-(OH)2D3 on T cells are mediated solely through monocytes, and it is possible that the hormone also exerts its influence directly on T cells.

The effect of 1,25-dihydroxyvitamin D3 on lymphoma cell lines and expression of vitamin D receptor in lymphoma

“…(Umetsu et al, 1990) indicating a possible role for CD4+T cells in promoting follicular NHL. 1,25(OH)2D3 inhibits CD4+T cell proliferation over a concentration range I0-'-10-1 M and this effect on CD4+T cells appears to be both direct and also indirect through suppression of ILl production by monocytes (Jordan et al, 1990;Tsoukas et al, 1989;Rigby, 1988;Binderup, 1992). Therefore the antifollicular NHL effect of 1,25(OH)2D3 may be mediated (at least in part) by an inhibitory effect on CD4+T cells.…”

“…The presence of the VDR in cells of the immunohaemopoetic system first indicated 1,25(OH)2D3 may have a role in regulating their activity. 1,25(OH)2D3 has been shown in vitro to have an antiproliferative effect and promote differentiation in monoblastic and promyelocytic cell lines, to inhibit differentiation in K562 leukaemia cells, to inhibit IL-1 production, to suppress CD4+T cell proliferation and IL2 production and inhibit immunoglobulin production by B cells (Jordan et al, 1990;Rebel et al, 1992;Tsoukas et al, 1989;Rigby et al, 1987;Moore et al, 1991;Iho et al, 1986;Tsoukas et al, 1984;Bhalla et al, 1989). In a number of cell lines the degree of response to 1,25(OH)2D3 appears to be dependent on the level of ligand binding (Chen et al, 1986) however the precise relationship is unknown.…”

Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis

“…Several studies have shown that 1,25-dihydroxyvitamin D 3 inhibits lymphocyte activation and dendritic cell maturation in addition to affecting other players of the immune system, such as cytokine and immunglobulin production and MHC class II expression. [22][23][24][25][26][27]52 In animal models the development of diabetes mellitus and encephalomyelitis can be prevented by the administration of 1,25-dihydroxyvitamin D 3 . 29,30 In this study, we provide evidence for an association of the BsmI and TaqI VDR polymorphisms in German patients with PBC.…”

“…18-21 1,25-dihydroxyvitamin D 3 leads to the decreased production of a number of cytokines, including IL-1, IL-2, IL-6, and IL-12, as well as TNF-␣ and -␤, and interferon gamma. [22][23][24][25][26][27] Apart from decreasing cytokine production, 1,25-dihydroxyvitamin D 3 is believed to act primarily by increasing anti-inflammatory cytokines such as IL-4 and transforming growth factor ␤. 28 A role of the VDR in autoimmune disease has been suggested experimentally in animal models.…”

A Method of Trigonometric Modelling of Seasonal Variation Demonstrated with Multiple Sclerosis Relapse Data

“…Several vitamin D-mediated immunomodulatory correlates with MS relapse onset probability have previously been observed including shifting T helper lymphocytes away from a pro-inflammatory Th1 profile to the less inflammatory Th2 [43][44][45][46] and inhibition of dendritic cells and IgM/IgG antibody production 43,[47][48][49][50] . Coupling this to the observation of a potential role for both season and latitude in the kinetics of relapse timing, this suggests a role in clinical practice for latitude-specific, location-appropriate vitamin D supplementation for reducing the probability of future relapse.…”