Regulation of microglial activation by TGF-β, IL-10, and CSF-1

Abstract

Microglia are the resident macrophages of the brain and as such are active participants in immune responses in the central nervous system. Normal resting microglia express low levels of MHC class I and class II antigens and do not produce proinflammatory cytokines. However, microglial immune functions are induced in areas of infection or injury. To understand regulation of cytokines that are secreted by and act upon microglia, we examined production of interleukin (IL) -12, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) by lipopolysaccharide (LPS)-stimulated microglia. We observed secretion of IL-12, TNF-alpha, and NO following stimulation of microglia with LPS. Addition of IL-10 suppressed TNF-alpha, IL-12, and NO production. Transforming growth factor-beta (TGF-beta) also inhibited TNF-alpha and NO but did not affect IL-12 secretion. IL-12 secretion became sensitive to TGF-beta inhibition when microglia were cultured in the absence of CSF-1. In addition to its effect on the response to TGF-beta, CSF-1 suppressed the response of microglia to LPS. These data suggest that CSF-1 may contribute to the immunologically privileged status of the central nervous system.

Mechanism of inhibition of LPS-induced IL-12p40 production by IL-10 and TGF-β in ANA-1 cells

“…We showed earlier that LPS-induced IL-12p40 production was decreased in murine microglial, macrophage, and ANA-1 cells after treatment with IL-10 or TGF-␤ [26]. This study defines the molecular mechanisms by which IL-10 and TGF-␤ exhibit these functions.…”

“…The amount of IL-12p40 production in culture supernatants was measured by an ELISA as described previously [26]. Briefly, monoclonal rat anti-murine IL-12p40 antibody (C17.15) was coated on an ELISA plate at 2.0 µg/mL in carbonate buffer (pH 9.6) overnight at 4°C and excess antibody was removed by washing with phosphate-buffered saline (PBS) containing 0.05% Tween-20 (PBST).…”

“…In addition, in vivo treatment of animals with TGF-␤ and IL-10 results in the inhibition of two well-defined Th1-mediated autoimmune diseases, experimental allergic encephalitis and collagen-induced arthritis [22][23][24][25]. We had earlier shown that TGF-␤ and IL-10 inhibited LPS-induced IL-12 production in microglial cells and macrophages [26]. We proposed that TGF-␤ and IL-10 regulated immune responses in vivo at least in part by suppressing IL-12 production in macrophages and other antigen-presenting cells.…”

Differential Regulation and Function of Fas Expression on Glial Cells

“…TGF-␤ inhibits IFN-␥-induced class II MHC and CD40 expression by microglia (27,56,57). As well, TGF-␤ inhibits TNF-␣, IL-1, IL-6, and IL-12 production by microglia (56,58). These results in conjunction with our findings that TGF-␤ inhibits cell death of microglia suggest that TGF-␤ expression at the recovery phase of EAE can protect microglia from cell death as well as inhibit their ability to function as an APC within the CNS.…”

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…Microglia synthesize and secrete TGF-b1 in response to inflammatory cytokines such as type I interleukin (IL-1), IL-6, nerve growth factor (NGF) and tumor necrosis factor-a (TNF-a) (Lindholm et al 1992b;da Cunha et al 1993;Chao et al 1995a,b). TGFb1 inhibits free radical induction and induces apoptosis, and TGF-b signaling through Smad2 and/or Smad3 is necessary for maintaining quiescent microglia populations after injury (Suzumura et al 1993;Lodge and Sriram 1996;Herrera-Molina and von Bernhardi 2005;Abutbul et al 2012). Extensive microgliosis is observed in the neocortex and hippocampus in Tgfb1 2/2 mice, whereas one allele of Tgfb1 is sufficient to reverse the phenotype (Brionne et al 2003).…”