Inflammatory Signals Induce Neurotrophin Expression in Human Microglial Cells

Abstract

Inflammatory processes involving reactive microglia, e.g., those associated with /1-amyloid containing neuritic and core plaques in Alzheimer's disease, appear to contribute to neuronal degeneration in the CNS. The fact that increased nerve growth factor (NGF) protein levels were found throughout brains of Alzheimer's disease patients led us to investigate neurotrophin synthesis in a human microglial cell line showing typical properties of human microglial cells, including expression of neurotrophins such as NGF, as well as the NGF receptor trkA and the low-affinity neurotrophin receptor p75. We found that the cytokines interleukin-1/3 and tumor necrosis factor-a synergistically stimulate microglial NGF transcription and protein release. Moreover, exposure of microglial cells to complement factor C3a induces NGF expression. To assess the role of the transcription factor nuclear factor-KB (NF-KB) in inflammatory mediator-induced microglial NGF expression, the effect of the NF-KB inhibitor pyrrolidine dithiocarbamate (PDTC) was analyzed. In the presence of PDTC, a dose-dependent inhibition of cytokine-activated NGF expression occurred. In contrast, the C3a-dependent stimulation of NGF synthesis was not influenced by PDTC. In addition, microglial neurotoxicitymediating /3-amyloid peptides A/1(1-40) and A~3(1-42) failed to alter NGF synthesis, whereas A/9(25-35) specifically induced NF-KB-dependent microglial NGF expression. In conclusion, inflammatory signals (cytokines and complement factors), as well as A/3(25-35), are potent stimulators of human microglial NGF synthesis involving NF-KB-dependent and -independent mechanisms. Microglial secretion of neurotrophins appears to be involved in early processes of neuronal regeneration. Key Words: Nerve growth factor-Cytokines-Complement factors-Alzheimer's disease. J. Neurochem. 70, 699-707 (1998).ing free oxygen intermediates, proteases, excitatory amino acids, arachidonic acid derivatives, and cytokines, and have been implicated in the destruction of neurons in trauma (Banati et al., 1993;Thanos et al., 1993), Alzheimer's disease (McGeer et al., 1987(McGeer et al., , 1993 Giulian et al., 1995Giulian et al., , 1996McGeer and McGeer, 1995;Kaltschmidt et al., 1997), and human immunodeficiency virus infection (Giulian et al., 1990;Dickson et al., 1993). Moreover, in vitro studies have revealed that microglia/brain macrophages can secrete growth factors [e.g., basic fibroblast growth factor and nerve growth factor (NGF) 1~known to enhance survival and fiber outgrowth of different types of CNS neurons Mallat et al., 1989;Shimojo et al., 1991;Araujo and Cotman, 1992;Elkabes et al., 1996). For their survival and maintenance of function, several classes of neurons rely on the continuous supply of neurotrophic factors, including NGF. After injury, increased synthesis of NGF occurs in glial cells and in target tissues (Thoenen and Barde, 1980;Levi-Montalcini and Calissano, 1986; Levi-Montalcmi, 1987). In response to CNS injury, both microglia and astrocytes undergo str...

Peripheral Blood Leukocyte Production of BDNF following Mitogen Stimulation in Early Onset and Regressive Autism

“…Further evidence of altered immune activation in autism includes proinflammatory cytokines, including TNFα, which has been shown to be increased in plasma and blood lymphocytes of autistic individuals [47][48][49] . These proinflammatory cytokines have been linked with increased secretion of neurotrophic factors [47][48][49][50][51][52] , which are critical regulators of synaptic development and maintenance, as well as neuron survival and differentiation [53,54] . In response to administered proinflammatory cytokines IL-6 and TNF , but not to Th1 and Th2 cytokines, BDNF expression is induced in human monocytes [50] .…”

Macrophages and HIV-1: dangerous liaisons

“…These molecules interact closely with inflammatory factors. For example, IL-1, TNF- and LPS induce or increase the expression of the nerve growth factor (NGF) by microglia through a NFB-dependent mechanism (Heese et al, 1998a;Heese et al, 1998b;Lindholm et al, 1987;Mallat et al, 1989;Nakajima et al, 2001), whereas the complement component C3a has the same effect independently of NFB activation (Heese et al, 1998b).…”

Revisiting the Koebner Phenomenon

“…1 Numerous cytokines such as interleukin (IL)-1, tumor necrosis factor (TNF)-␣, and IL-6 can induce NGF production in fibroblasts, endothelial cells, and glial cells. 2,3 In addition, immune cells involved in innate and acquired immunity show a basal level of NGF expression. NGF synthesis in these cells is enhanced after stimulation with specific antigens and cytokines.…”

“…NGF synthesis in these cells is enhanced after stimulation with specific antigens and cytokines. [1][2][3] The immune cells that produce NGF also express the specific NGF receptor TrkA that, on binding to its ligand, activates intracellular pathways and nuclear factors in a manner similar to what happens in neuronal cells. In vitro, the administration of NGF to purified myeloid or lymphoid cell populations influences a wide range of functions: the release of inflammatory mediators, chemotaxis, the production of cytokines and immunoglobulins, proliferation, and survival of cells.…”

“…In vitro, the administration of NGF to purified myeloid or lymphoid cell populations influences a wide range of functions: the release of inflammatory mediators, chemotaxis, the production of cytokines and immunoglobulins, proliferation, and survival of cells. [1][2][3] Thus, NGF may influence the inflammatory process either directly by regulating immune cell functions, or indirectly, by modulating neuropeptide synthesis, which in turn induces an inflammatory reaction. These evidences have led to the current concept that either de novo synthesis of NGF or up-regulation of induced NGF by proinflammatory cytokines such as TNF-␣, IL-1, or IL-6 plays a critical role in initiation, maintenance, and perpetuation of a chronic inflammatory process.…”