S100B binding to RAGE in microglia stimulates COX-2 expression

Abstract

Besides exerting regulatory roles within astrocytes, the Ca2+-modulated protein of the EF-hand type S100B is released into the brain extracellular space, thereby affecting astrocytes, neurons, and microglia. However, extracellular effects of S100B vary, depending on the concentration attained and the protein being trophic to neurons up to nanomolar concentrations and causing neuronal apoptosis at micromolar concentrations. Effects of S100B on neurons are transduced by receptor for advanced glycation end products (RAGE). At high concentrations, S100B also up-regulates inducible NO synthase in and stimulates NO release by microglia by synergizing with bacterial endotoxin and IFN-gamma, thereby participating in microglia activation. We show here that S100B up-regulates cyclo-oxygenase-2 expression in microglia in a RAGE-dependent manner in the absence of cofactors through independent stimulation of a Cdc42-Rac1-JNK pathway and a Ras-Rac1-NF-kappaB pathway. Thus, S100B can be viewed as an astrocytic endokine, which might participate in the inflammatory response in the course of brain insults, once liberated into the brain extracellular space.

S100B Inhibition Reduces Behavioral and Pathologic Changes in Experimental Traumatic Brain Injury

“…7,40 TNF-α has an important role in S100B release from the astrocytes, suggesting that TNF-α might elevate the extracellular concentration of S100B favoring activating effects of S100B on microglia. 7,40 Collectively, our data and previously demonstrated mechanisms indicate that S100B contributes to the activation and progression of neuroinflammatory processes following TBI. However, S100B inhibition may directly or indirectly attenuate neuroinflammation after TBI, and future studies are needed to determine the mechanisms of S100B-mediated neuroinflammatory effects.…”

“…6 In contrast, as an extracellular factor S100B interacts with advanced glycation end product-specific receptor (AGER) to exert beneficial or detrimental effects, or pro-proliferative or pro-differentiative consequences based on its concentration and microenvironment. 7,8 In addition to its expression in astroglia and Schwann cells, S100B has also been found in adipocytes, chondrocytes, cardiomyocytes, lymphocytes, bone marrow cells, and melanocytes where it exerts intracellular and extracellular functions. 6 Therefore, both CNS and circulatory S100B exert the same functions that are dependent on their concentration and may serve as important biomarkers of CNS injury.…”

“…16 AGER is a member of the immunoglobulin (Ig) family of cell surface molecules that recognizes multiple ligands, including AGE, amphoterin, amyloid-β-peptide and β-fibrils, and S100B. Extracellular S100B has been observed to exhibit trophic effects on neurons by interaction with AGER, 7,8 which has been implicated in neuroprotection and neurodegeneration as well as in inflammatory responses. 17 S100B at high concentrations via acute stimulation of AGER causes neuronal apoptosis by excessive extracellular signal-regulated kinase 1 (ERK1)/2 activation and overproduction of reactive oxygen species (ROS).…”

“…17 S100B at high concentrations via acute stimulation of AGER causes neuronal apoptosis by excessive extracellular signal-regulated kinase 1 (ERK1)/2 activation and overproduction of reactive oxygen species (ROS). 7 In our study, we evaluated the effects of S100B inhibition using either a knockout model or administration of a neutralizing S100B antibody in a mouse model of controlled cortical impact (CCI). Furthermore, we investigated the potential interaction of S100B with AGER in CCI, as well as the effects of S100B on primary microglial cultures or a mouse microglial cell line after activation with lipopolysaccharide (LPS) or interferon gamma (IFNγ).…”

S100B protein in serum is elevated after global cerebral ischemic injury

“…It has been shown that S100B is only expressed by a subtype of mature astrocytes that ensheath blood vessels and by NG2-expressing cells. Recent studies[4,5] have provided more detailed information about the mechanism (s) of action of S100B as an intracellular regulator and an extracellular signal. Intracellular S100B acts as a stimulator of cell proliferation and migration and an inhibitor of apoptosis and differentiation, which might have important implications during the development and repair of the brain, cartilage and skeletal muscle, the activation of astrocytes in the course of brain damage and neurodegenerative processes, and the remodeling of cardiomyocytes after infarction as well as in melanomagenesis and gliomagenesis.…”