Regulatory Activity of Autocrine IL-10 on Dendritic Cell Functions

411

340

The functions of dendritic cells (DCs) are tightly regulated such that protective immune responses are elicited and unwanted immune responses are prevented. 1α25-dihydroxyvitamin D3 (1α25(OH)2D3) has been identified as a major factor that inhibits the differentiation and maturation of DCs, an effect dependent upon its binding to the nuclear vitamin D receptor (VDR). Physiological control of 1α25(OH)2D3 levels is critically dependent upon 25-hydroxyvitamin D3-1α-hydroxylase (1αOHase), a mitochondrial cytochrome P450 enzyme that catalyzes the conversion of inactive precursor 25-hydroxyvitamin D3 (25(OH)D3) to the active metabolite 1α25(OH)2D3. Using a human monocyte-derived DC (moDC) model, we have examined the relationship between DC VDR expression and the impact of exposure to its ligand, 1α25(OH)2D3. We show for the first time that moDCs are able to synthesize 1α25(OH)2D3 in vitro as a consequence of increased 1αOHase expression. Following terminal differentiation induced by a diverse set of maturation stimuli, there is marked transcriptional up-regulation of 1αOHase leading to increased 1αOHase enzyme activity. Consistent with this finding is the observation that the development and function of moDCs is inhibited at physiological concentrations of the inactive metabolite 25(OH)D3. In contrast to 1αOHase, VDR expression is down-regulated as monocytes differentiate into immature DCs. Addition of 1α25(OH)2D3 to moDC cultures at different time points indicates that its inhibitory effects are greater in monocyte precursors than in immature DCs. In conclusion, differential regulation of endogenous 1α25(OH)2D3 ligand and its nuclear receptor appear to be important regulators of DC biology and represent potential targets for the manipulation of DC function.

Section: Discussionsupporting

confidence: 51%

Differential Regulation of Vitamin D Receptor and Its Ligand in Human Monocyte-Derived Dendritic Cells

Hewison

Freeman²,

Hughes

et al. 2003

411

340

“…This suggests that there are other cytokines involved in the regulation of the IgE response in this model. Some evidence suggests that IL-10 can down-regulate allergic hyperreactivity via direct effects on both DC (34,35) and mast cells (36). However, no study has yet demonstrated a mechanism by which helminth-induced immunoregulation directly affects the induction of allergic disease.…”

Section: Discussionmentioning

confidence: 99%

An Enteric Helminth Infection Protects Against an Allergic Response to Dietary Antigen

Bashir

Andersen

Fuss

et al. 2002

215

161

Although helminths induce a polarized Th2 response they have been shown, in clinical studies, to confer protection against allergies. To elucidate the basis for this paradox, we have examined the influence of an enteric helminth infection on a model of food allergy. Upon Ag challenge, mice fed peanut (PN) extract plus the mucosal adjuvant cholera toxin (CT) produced PN-specific IgE that correlated with systemic anaphylactic symptoms and elevated plasma histamine. PN-specific IgE was not induced in helminth-infected mice fed PN without CT. Moreover, when PN plus CT was fed to helminth-infected mice, both PN-specific IgE and anaphylactic symptoms were greatly diminished. The down-regulation of PN-specific IgE was associated with a marked reduction in the secretion of IL-13 by PN-specific T cells. When helminth-infected PN plus CT-sensitized mice were treated with neutralizing Abs to IL-10, the PN-specific IgE response and anaphylactic symptoms were similar to, or greater than, those seen in mice that receive PN and CT alone. Taken together, these results suggest that helminth-dependent protection against allergic disease involves immunoregulatory mechanisms that block production of allergen-specific IgE.

“…It has recently been demonstrated that a distinct subset of DCs with the phenotype CD11c low CD45RB high has the ability to secrete IL-10 and induce tolerance and T regulatory cell differentiation (65). It has also been shown that IL-12 production by immature DCs is susceptible to inhibition by IL-10-producing T regulatory cells (66,67). In addition, DCs induce selective expansion of regulatory T cells, producing immunosuppressive cytokines such as IL-10 and TGF-␤ (68 -70).…”

Section: Discussionmentioning

confidence: 99%

Flt-3 Ligand Reverses Late Allergic Response and Airway Hyper-Responsiveness in a Mouse Model of Allergic Inflammation

Edwan

Perry²,

Talmadge

et al. 2004

Flt3 ligand (Flt3-L) is a growth factor for dendritic cells and induces type 1 T cell responses. We recently reported that Flt3-L prevented OVA-induced allergic airway inflammation and suppressed late allergic response and airway hyper-responsiveness (AHR). In the present study we examined whether Flt3-L reversed allergic airway inflammation in an established model of asthma. BALB/c mice were sensitized and challenged with OVA, and AHR to methacholine was established. Then mice with AHR were randomized and treated with PBS or 6 μg of Flt3-L i.p. for 10 days. Pulmonary functions and AHR to methacholine were examined after rechallenge with OVA. Treatment with Flt3-L of presensitized mice significantly suppressed (p < 0.001) the late allergic response, AHR, bronchoalveolar lavage fluid total cellularity, absolute eosinophil counts, and inflammation in the lung tissue. There was a significant decrease in proinflammatory cytokines (TNF-α, IL-4, and IL-5) in bronchoalveolar lavage fluid, with a significant increase in serum IL-12 and a decrease in serum IL-5 levels. There was no significant effect of Flt3-L treatment on serum IL-4 and serum total IgE levels. Sensitization with OVA significantly increased CD11b+CD11c+ cells in the lung, and this phenomenon was not significantly affected by Flt3-L treatment. These data suggest that Flt3-L can reverse allergic airway inflammation and associated changes in pulmonary functions in murine asthma model.