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Modulation of interleukin-1 and tumor necrosis factor expression by beta-adrenergic agonists in mouse ameboid
E Hetier1, J Ayala, A Bousseau
1CNRS URA 1414, Ecole Normale Supérieure, Paris, France.
Abstract:
Brain macrophages (ameboid microglial cells) purified to homogeneity and cultured in vitro synthesize and release IL-1 and TNF upon stimulation with lipopolysaccharide (LPS). This induction can be measured at the levels of transcription and translation. In the present study we have analysed whether certain compounds normally present in the nervous tissue could regulate cytokine production by brain macrophages. We demonstrate that the beta-adrenergic agonist isoproterenol, at a concentration of 10(-7) M; inhibits the LPS-induced transcription and release of TNF alpha. At the same concentration, isoproterenol increases the accumulation of IL-1 alpha and IL-1 beta mRNAs. In spite of its strong effect on IL-1 mRNA accumulation, the adrenergic agonist did not enhance IL-1 activity produced by microglial cells. On the contrary, as is the case for TNF, the LPS-induced production of IL-1 was inhibited by isoproterenol. The effects of isoproterenol on cytokine production specifically involve the beta 2 and not the beta 1 adrenergic receptor. It thus appears (i) that the accumulation of mRNAs coding for TNF alpha on one hand and IL-1 alpha and beta on the other is regulated in two opposite ways by the stimulation of the beta 2-adrenergic receptor and (ii) that mRNA accumulation and cytokine production and secretion are not necessarily coupled.
Insights
Beta-adrenergic agonists like isoproterenol differentially regulate brain macrophage cytokine production. Isoproterenol inhibits TNF-alpha and IL-1 production, despite increasing IL-1 mRNA levels.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
Background:
- Brain macrophages, or microglial cells, are key immune cells in the central nervous system.
- Microglia produce inflammatory cytokines like Interleukin-1 (IL-1) and Tumor Necrosis Factor-alpha (TNF-alpha) upon stimulation with lipopolysaccharide (LPS).
- The regulation of cytokine production by endogenous nervous system compounds is not fully understood.
Purpose of the Study:
- To investigate the effect of the beta-adrenergic agonist isoproterenol on cytokine production by brain macrophages.
- To determine the specific adrenergic receptor subtypes involved in this regulation.
- To elucidate the relationship between mRNA accumulation and cytokine release.
Main Methods:
- Primary cultures of purified brain macrophages (microglial cells).
- Stimulation with lipopolysaccharide (LPS) in the presence or absence of isoproterenol.
- Analysis of cytokine mRNA levels (transcription) and protein release (translation).
- Pharmacological characterization using beta 1 and beta 2 adrenergic receptor antagonists.
Main Results:
- Isoproterenol (10(-7) M) inhibited LPS-induced TNF-alpha transcription and release.
- Isoproterenol increased IL-1 alpha and IL-1 beta mRNA accumulation but did not enhance IL-1 activity.
- Both TNF-alpha and IL-1 production were ultimately inhibited by isoproterenol.
- The observed effects were mediated specifically through beta 2-adrenergic receptors.
Conclusions:
- Beta 2-adrenergic receptor stimulation differentially regulates cytokine mRNA levels, oppositely affecting TNF-alpha and IL-1.
- mRNA accumulation does not always correlate with actual cytokine production and secretion.
- Endogenous beta-adrenergic signaling pathways represent a potential regulatory mechanism for neuroinflammation.