TGF-β and Vitamin D3 Utilize Distinct Pathways to Suppress IL-12 Production and Modulate Rapid Differentiation of Human Monocytes into CD83+ Dendritic Cells

Abstract

We previously demonstrated that agents known to signal infection or inflammation can rapidly and directly drive differentiation of human CD14+ monocytes into CD83+ dendritic cells (DCs) when introduced to cells under serum-free conditions. In this study, we evaluated the effects of TGF-β and vitamin D3 (VitD3) on the proportion and function of monocytes that adopt DC characteristics. TGF-β significantly decreased the proportion of cells that rapidly adopted stable DC characteristics in response to LPS, but had little or no effect on calcium ionophore-induced differentiation. In contrast, VitD3 showed no such pathway specificity and dramatically suppressed differentiation of monocytes into DCs in response to these agents. Both TGF-β and VitD3 altered cytokine and chemokine production in LPS-treated monocytes, inhibited IL-12 and IL-10 secretion, and decreased the functional capacity of DCs. Despite the similar effects of TGF-β and VitD3, there are significant differences in the signaling pathways used by these agents, as evidenced by their distinct effects on LPS- and calcium ionophore-induced DC differentiation, on LPS-induced secretion of IL-10, and on two members of the NF-κB family of transcription factors, RelB and cRel. These studies identify TGF-β and VitD3 as potent regulatory factors that use distinct pathways to suppress both the differentiation of DCs as well as their capacity to secrete the Th1-polarizing cytokine IL-12. Because these agents are present in serum and negatively affect DC differentiation at physiological concentrations, our findings are likely to have significance regarding the in vivo role of TGF-β and VitD3 in determining the type of immune responses.

Complement Receptor 3 Ligation of Dendritic Cells Suppresses Their Stimulatory Capacity

“…TGF-␤ is a potent immunomodulatory cytokine that has been associated with regulatory T cell induction (29) as well as multiple other effects (27,28,30). We could speculate a role for this TGF-␤ in the blunted T cell responses seen in CR3-ligated BMDCs, though it is difficult to invoke a role for regulatory T cells in the blunted CD8 response as there were no CD4 cells present in these cultures.…”

Smad7 Gene Therapy Ameliorates an Autoimmune Crescentic Glomerulonephritis in Mice

“…In addition, TGF-␤ can induce its downstream inhibitory Smad7, which in turn inhibits Smad2/3 phosphorylation via the negative feedback mechanisms (9,10). In the context of immune and inflammation, TGF-␤ plays a critical role in negatively modulating the immune and inflammatory response (11). This is demonstrated by the observations that mice that lack TGF-␤ develop uncontrollable systemic inflammation and die in 3 wk after birth (12).…”

Inhibition of NF-κB and Oxidative Pathways in Human Dendritic Cells by Antioxidative Vitamins Generates Regulatory T Cells

“…These include vitamin D. The biologically active form of this vitamin, 1␣,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) (or its analogues), can block both monocyte differentiation into DC and the activation of DC (51)(52)(53)(54)(55) at least in part by inhibition of the NF-B pathway (56,57). T cells exposed to 1,25(OH) 2 D 3 -treated DC are unresponsive (58,59), may undergo apoptosis (58 -60), can be anergic to subsequent stimulation with Ag (51,59,61), and can adopt a regulatory phenotype (59,61).…”