Exposure of Myeloid Dendritic Cells to Exogenous or Endogenous IL-10 during Maturation Determines Their Longevity

Abstract

Dendritic cells (DC) are essential for the initiation of primary adaptive immune responses, and their functionality is strongly down-modulated by IL-10. Both innate and adaptive immune signals trigger the up-regulation of antiapoptotic Bcl-2 family members to facilitate the survival of DCs after maturation. However, whether IL-10 alters the expression of apoptotic-related genes in maturing DCs has not been determined. In this study, we demonstrate that spontaneous apoptosis rapidly occurred in myeloid DCs exposed to exogenous IL-10 upon maturation. Microarray analysis indicates that IL-10 suppressed the induction of three antiapoptotic genes, bcl-2, bcl-x, and bfl-1, which was coincident with the increased sensitivity of mature DCs to spontaneous apoptosis. IL-10 markedly inhibited the accumulation of steady state Bcl-2 message and protein in myeloid DCs activated through TLRs or TNFR family members, whereas exogenous IL-10 affected Bcl-xL expression in a moderate manner. In contrast, bcl-2 expression of plasmacytoid DCs was less sensitive to the effects of IL-10. We further show that autocrine IL-10 significantly limited the longevity of myeloid DCs and altered the expression kinetics of Bcl-2 but not Bcl-xL in maturing DCs. We conclude that the degree of IL-10 exposure and/or the level of endogenous IL-10 production upon myeloid DC maturation play a critical role in determining DC longevity. This regulatory mechanism of IL-10 is associated with the dynamic control of antiapoptotic Bcl-2 proteins.

Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

“…In addition, TAK1 was required for NF-κB activity in DCs. Moreover, TAK1-deficient DCs showed an enhanced autocrine IL-10 signaling, which likely further contributed to the increased cell death, given the important role of IL-10 in promoting DC apoptosis (64). Taken together, TAK1 affects signal transduction and gene expression of both proapoptotic and antiapoptotic pathways and further links them with expression of immune response genes, thereby orchestrating a prosurvival program in DCs.…”

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

“…The evidence presented here, along with other studies on cmvIL-10 and rhcmvIL-10, lead to the following model invoking a temporal race between dissemination of virus to sites of persistence and generation of protective adaptive immune responses. Expression of rhcmvIL-10 in the control animals suppresses innate effector cells at the primary site of infection to enable dissemination to sites of persistent shedding in the salivary glands and genitourinary tract prior to development of protective adaptive responses (15,(17)(18)(19)(59)(60)(61). In contrast, vaccine-mediated neutralization of rhcmvIL-10 facilitates innate effector functions to greatly restrict robust dissemination of progeny virions until development of protective adaptive responses blocks further dissemination.…”

Immune Activation and Regulation in Simian Immunodeficiency Virus-Plasmodium fragile-Coinfected Rhesus Macaques

“…Contrary to mDC, peripheral blood Mo of SIV-P. fragile-infected animals were able to maintain or even slightly increase TLR responses throughout infection and produced IL-10 in addition to TNF-␣ and IL-12. Interestingly, IL-10 has been implicated in promoting the differentiation of peripheral Mo toward a macrophage phenotype while simultaneously inhibiting mDC maturation (36)(37)(38)58). The potential role of IL-10 in the suppression of mDC function in SIV-P. fragilecoinfected animals was supported by the fact that the loss of peripheral blood mDC function was temporarily associated with parasitemia.…”

“…2B). IL-10 has been shown to promote the differentiation of peripheral Mo toward a macrophage phenotype while simultaneously inhibiting mDC maturation (36)(37)(38), and this might explain the observed divergent TLR response patterns in Mo versus mDC. SIV-infected animals maintained Mo TNF-␣ responses at or slightly above preinfection levels throughout infection (Fig.…”