APC can directly produce many cytokines and chemokines during the innate immune response as well as promote effective antigen presentation in acquired adaptive immunity. IL-10 inhibits the expression of cytokines, soluble mediators and cell surface molecules by mono-cytes, macrophages, and myeloid DC (Fig. 1).39,40,79-81 IL-10 is able to prevent monocyte differentiation into myeloid DC, which are the most important APCs, especially for primary immune responses. IL-10 inhibits the inflammatory or specific cellular immune response, and these effects are regulated with the induction of tolerance in adaptive immunity. IL-10 modulates the resultant cytokine cascade which develops in vivo. It inhibits the production of proinflammatory mediators by monocytes and macrophages including endotoxin- and IFN-Y-induced release of IL-1a, IL-1p, IL-6, IL-8, IL-10 itself, IL-12, IL-18, M-CSF, G-CSF, GM-CSF, TNF, LIF and PAF.2,82 Moreover, IL-10 inhibits the production of IL-12 by monocytes or myeloid DC, which is an essential mediator for the development of specific cellular immune defense. In the innate immune response of the parasitic protozoa models,83 macrophages and DC are impaired in the production of IL-12 and migration, but not equally. For example, IL-12 production is actively suppressed in macrophages infected with L. major or 77 gondii, whereas DC produce IL-12p40 in response to the same parasites, both in vitro and in vivo.83-85 However, endogenous agonists such as CD40L or IFN-y are necessary as costimuli to induce high levels of IL-12 production. Either decrease of IL-12 or increase of IL-10 are observed in infected DC, and they inhibit the resultant T cell immune response.
Effects of IL-10 on Monocytes, Macrophages
IL-10 upregulates expression of the fMLP receptor, the PAF receptor, and the CCR1, CCR2, and CCR5 receptors on monocyes, making these cells more responsive to chemotactic factors and thereby more susceptible to HIV infection (e.g., IL-12 inhibits CCR5 expression by monocytes).2,86- 9 IL-10 enables monocytes conversion to a macrophage phenotype not only by directly suppressing function, but also by enhancing the production of anti-inflammatory molecules including interleukin-1 receptor antagonist (IL-1RA or receptors) including the soluble p55 and p75 TNFR and the IL-1RI and IL-1RII receptors.90-95 Pretreatment of monocytes with chemokines including MCP1-4 suppressed production of IL-12p70 as a result of the induction of endogenous IL-10 production.96 IL-10 inhibited production of prostaglandin E2 (PGE2), through downregulation of cyclooxygenase 2 (COX-2) expression.97- Despite down regulation of T cell responses, IL-10 up-regulated the phagocytic activity of monocytes, macrophages, and immature DC via up-regulation ofexpression of IgG-Fc receptors (CD16, CD32, and CD64) as well as scavenger receptors (CD163 and CD14).100
Dying cells use both recruitment and "eat-me" signals for phagocyte attraction and recognition. Annexin I is a phosphatidylserine [PS] binding soluble protein. PS apprears to be a key molecule "exposed" on the surface of apoptotic cells that facilitates their phagocytic recogni-tion.101 During enhancement of the phagocytic activity of monocytes/macrophages for opsonized particles, bacteria, or fungi, Annexin I reduces the ability of cells to kill ingested organisms by decreasing generation of superoxide anion (O2-) and nitric oxide (NO). This mechanism involves inhibition of endogenous cytokine (TNF-a, IFN-y) synthesis. Ligation of CD23 or CD64 induces expression of IL-10 by monocytes. IL-10 also downregulates expression ofTLR4, the signal transducing receptor for LPS, and enhances expression of CD14, CD16, CD64, and CD163, a scavenger receptor that is downregulated by LPS, IFN-y and TNF-a.100,102 Collectively, these observations indicate that IL-10 induces differentiation of a macrophage-like cell, but limits ongoing immune responses and inflammation, and contributes to clearances of the infection via enhanced phagocytosis. Both IL-10 and TGF-P are produced by murine macrophages after Leishmania infection in vitro, promoting replication within macrophages and are important factors for determining in vivo susceptibility to infection.103,104 After infection, IL-10 producing APC become competent for protozoa or virus replication.
Mouse and human DC are defined by their ability to activate and prime naive resting T cells and initiate immune responses. As IL-10 inhibited production of IL-12 and expression of costimulatory molecules by various types of DC,105-108 its expression correlated with inhibition of primary alloantigen-specific T cell responses. IL-10 treatment of DC can induce or contribute to a state of anergy in allo-antigen- or peptide-antigen-activated CD4+ and CD8+ T cells.2,39,40
Immature DC cultured human monocytes with GM-CSF and IL-4 for 6 days can be matured by LPS, CD40 ligand, or TNF-a to secrete IL-12 and induce differentiation of naive T cells to Th1 cells. The peptide-specific T cells induced by immature DCs, but not mature DCs were indeed able to suppress the effector function of IFN-y secreting cells.109 By adding IL-10 in culture with GM-CSF and IL-4, maturation of DC is inhibited (Fig. 1). Rather, this caused differentiation of the immature DC into macrophage-like cells that expressed reduced levels of costimulatory molecules and MHC class II, but increased expression of MCSF and MCSFR, did not produce IL-12, and exhibited enhanced phagocytosis.2 In contrast, IL-10 did not affect mature monocyte-derived DC; these cells may have lost IL-10R1 expression.110,111
IL-10 also affects CD4+CD11c-IL-3R+ plasmacytoid DC. They can produce large amounts of IFN-a after exposure to virus, and furthermore they differentiate in vitro with IL-3 and CD40L into plasmacytoid DCs that can support differentiation of Th2 cells. IL-10 induced apoptosis of both freshly isolated and cultured plasmacytoid DC.112 Myeloid DCs produce large amounts of IL-12 and induce strong Th1 and CTL response, while plasmacytoid DCs do not produce large amounts of IL-12, and induce Th2 responses, or the generation of IL-10-producing CD8+T suppressor cells. Unlike IL-3- and CD40L-induced plasmacytoid DCs, which promote Th2 responses, viral-induced plasmacytoid DCs promote naive T cells to produce both IFN-y and IL-10.113
Particular DC populations producing IL-10 have been identified in Payer's patches in intestine, liver, lung and monocyte-derived DC.2,114 In these organs, IL-10 plays a role to lead to tolerance in several ways: IL-10 can directly suppress T cells; IL-10 may be required to induce regulatory T cells; or IL-10 can act on DCs to decrease their function or make them tolerogenic. They are associated with development of either Th2 responses or hyporesponsiveness. In general, the effects of IL-10 on DC are consistent with inhibition of Th1 inflammatory responses and can be activated by inhibitory effects on "inflammation-inducing DC" or by induction of anti-inflammatory T cell populations by IL-10-producing DC. In the innate immunity of infectious disease, IL-10 is secreted by DC through microbial Toll-like receptor activators, such as LPS, gram positive bacterial peptide glycan (PGN), and yeast zymosan.115 Especially, two TLR2 agonists; PGN and yeast zymosan produced IL-10 in CD40-dependent manner. In contrast, IL-12 synthesis was seen in murine splenic DCs after injection of a soluble extract of T. gondii tachyzoites (STAg). The response was short-term and could not be released by a second injection of STAg for a period of 1 week after initial priming.83 This paralysis of the DC IL-12 response induced by STAg does not require IL-10 but instead appears to depend on the induction of lipoxin A4 (LXA4), a product of arachadonic metabolism. Infected DC produced IL-10 and reduced IL-12 leading to induction of IL-10 producing T cells. This balance help to reduce the innate immunity.
In several tumor models, IL-10 expressed within the tumors could drive rejection and elimination of the tumor, whereas the EBV expressed homologue, vIL-10 promoted tumor growth.58,116 In some models, IL-10 can promote the generation of nominally tolerogenic regulatory T cells.117 In this setting, tumor-infiltrating DCs (TIDCs) are largely immature, and are able to present tumor antigen, but they are refractory to stimulation with a combination of LPS, IFN-y, and anti-CD40 antibody. DC paralysis in this setting can be reversed by CpG plus anti-IL-10 R treatment. This combination, but not CpG alone, had a potent therapeutic antitumor effect and induce immune memory.118 In most tumor settings, IL-10 production has interestingly been associated with improved outcome in murine models and in predicting melanoma responsiveness to IL-10 therapy.119
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