Prolonged exposure of microglia to lipopolysaccharide modifies the intracellular signaling pathways and selectively promotes prostaglandin E₂ synthesis

Abstract

During inflammatory or degenerative processes microglial cells are likely to be exposed to activating agents that persist in brain parenchyma for prolonged periods. As our knowledge on microglial activation is largely based on in vitro studies in which microglial cultures are activated by a single administration of pro-inflammatory stimuli, we investigated the effects of repeated endotoxin (LPS) challenges on microglial functional state. Primary rat microglial cultures were subjected to one, two or three consecutive LPS-stimulation and the production of tumor necrosis factor-a (TNF-a), nitric oxide (NO), prostaglandin E 2 (PGE 2 ) and 15-deoxy-D 12,14 -PGJ 2 (15d-PGJ 2 ) measured. The ability of microglial cells to produce NO, TNF-a and 15d-PGJ 2 upon the first LPS challenge rapidly declined after the second and the third stimulations, whereas PGE 2 synthesis remained constantly elevated. Accordingly, the expression of inducible NO synthase decreased whereas cyclooxygenase-2 and microsomal PGE synthase remained up-regulated. The signaling pathways evoked by single or multiple LPS-stimulation were also profoundly different, when considering the activation of the transcription factors nuclear factor-kappa B and CREB, and of the p38 MAPK. Our observations suggest that prolonged exposure to LPS, and likely other activating agents, induces in microglia a functional state clearly distinct from that triggered by acute stimulation. The progressive down-regulation of proinflammatory molecules and the sustained release of PGE 2 could have important implications for the resolution of brain inflammation.

Regulation of Lentivirus Neurovirulence by Lipopolysaccharide Conditioning: Suppression of CXCL10 in the Brain by IL-10

“…The underlying neuroprotective defense mechanism in the present studies appeared to be dependent on CXCL10 suppression, perhaps by IL-10, which is known to occur as a consequence of LPS exposure (55,56), but other pathways including differential expression of PGE2 and other host cytokines are also regulated by chronic LPS exposure (57). Importantly, IL-10 is an anti-inflammatory cytokine that exerts effects on both systemic inflammation and neuroinflammation (58).…”

Role of Microglia in Central Nervous System Infections

“…Neisseria meningitidis and Haemophilus influenzae are the most important causes of gram-negative bacterial meningitis. The major component of the outer membrane of the gram-negative bacterial cell wall, LPS (302), is a potent stimulus of many secretory products of microglia including cytokines (TNF-␣, IL-1␤, and IL-6), chemokines, and prostaglandins (4,67,260) and often has been used for activation of microglia in vitro (260). Examples of microglial cell stimulation by LPS include the induction of the chemokines CXCL8/IL-8 ( Fig.…”

“…In contrast to microglial cells from adult brain tissue (357), amoeboid microglial cells express CD14 receptors, which, along with TLR4 (183), are the main plasma membrane binding sites for LPS-induced cytokine expression (117). Although LPS has been used as a classic activating agent, a recent study of rat microglia demonstrated that prolonged LPS exposure induces a distinctly different activated state from that in microglia acutely exposed to LPS (4). The microglial cells demonstrated a degree of adaptation to repetitive exposure to LPS, with diminishing TNF-␣ and NO, but persisting prostaglandin E 2 (PGE 2 ) production.…”

Possible involvement of 15‐deoxy‐Δ12,14‐prostaglandin J2 in the development of leptin resistance

“…Therefore, an increase in 15d-PGJ 2 levels in the brain may contribute to the development of leptin resistance. The production of 15d-PGJ 2 from microglia cells was shown to be elevated under inflammatory conditions (Ajmone-Cat et al 2003). Since chronic inflammation has been observed in the obese hypothalamus, microglia may induce the production of 15d-PGJ 2 , which may in turn be involved in the development of leptin resistance.…”

“…However, the mechanisms underlying the development of leptin resistance in an inflammatory state remain unclear. Since 15d-PGJ 2 is up-regulated in inflammation and may be critically involved in immune reactions (Ajmone-Cat et al 2003), we hypothesized that 15d-PGJ 2 may play a role in the development of leptin resistance. We herein described a novel mechanism for the development of obesity; i.e.…”