Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1β production
<p>Abstract</p> <p>Background</p> <p>Under pathological conditions, microglia produce proinflammatory mediators which contribute to neurologic damage, and whose levels can be modulated by endogenous factors including neurotransmitters such as norepinephrine (NE). We inv...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2004-06-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://www.jneuroinflammation.com/content/1/1/9 |
| _version_ | 1811295036231385088 |
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| author | Gavrilyuk Vitaliy Boullerne Anne I Dello Russo Cinzia Feinstein Douglas L |
| author_facet | Gavrilyuk Vitaliy Boullerne Anne I Dello Russo Cinzia Feinstein Douglas L |
| author_sort | Gavrilyuk Vitaliy |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Under pathological conditions, microglia produce proinflammatory mediators which contribute to neurologic damage, and whose levels can be modulated by endogenous factors including neurotransmitters such as norepinephrine (NE). We investigated the ability of NE to suppress microglial activation, in particular its effects on induction and activity of the inducible form of nitric oxide synthase (NOS2) and the possible role that IL-1β plays in that response.</p> <p>Methods</p> <p>Rat cortical microglia were stimulated with bacterial lipopolysaccharide (LPS) to induce NOS2 expression (assessed by nitrite and nitrate accumulation, NO production, and NOS2 mRNA levels) and IL-1β release (assessed by ELISA). Effects of NE were examined by co-incubating cells with different concentrations of NE, adrenergic receptor agonists and antagonists, cAMP analogs, and protein kinase (PK) A and adenylate cyclase (AC) inhibitors. Effects on the NFκB:IκB pathway were examined by using selective a NFκB inhibitor and measuring IκBα protein levels by western blots. A role for IL-1β in NOS2 induction was tested by examining effects of caspase-1 inhibitors and using caspase-1 deficient cells.</p> <p>Results</p> <p>LPS caused a time-dependent increase in NOS2 mRNA levels and NO production; which was blocked by a selective NFκB inhibitor. NE dose-dependently reduced NOS2 expression and NO generation, via activation of β2-adrenergic receptors (β2-ARs), and reduced loss of inhibitory IkBα protein. NE effects were replicated by dibutyryl-cyclic AMP. However, co-incubation with either PKA or AC inhibitors did not reverse suppressive effects of NE, but instead reduced nitrite production. A role for IL-1β was suggested since NE potently blocked microglial IL-1β production. However, incubation with a caspase-1 inhibitor, which reduced IL-1β levels, had no effect on NO production; incubation with IL-receptor antagonist had biphasic effects on nitrite production; and NE inhibited nitrite production in caspase-1 deficient microglia.</p> <p>Conclusions</p> <p>NE reduces microglial NOS2 expression and IL-1β production, however IL-1β does not play a critical role in NOS2 induction nor in mediating NE suppressive effects. Changes in magnitude or kinetics of cAMP may modulate NOS2 induction as well as suppression by NE. These results suggest that dysregulation of the central cathecolaminergic system may contribute to detrimental inflammatory responses and brain damage in neurological disease or trauma.</p> |
| first_indexed | 2024-04-13T05:26:30Z |
| format | Article |
| id | doaj.art-36ac29e101954bef9a41aaad8c5dcf42 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-13T05:26:30Z |
| publishDate | 2004-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-36ac29e101954bef9a41aaad8c5dcf422022-12-22T03:00:34ZengBMCJournal of Neuroinflammation1742-20942004-06-0111910.1186/1742-2094-1-9Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1β productionGavrilyuk VitaliyBoullerne Anne IDello Russo CinziaFeinstein Douglas L<p>Abstract</p> <p>Background</p> <p>Under pathological conditions, microglia produce proinflammatory mediators which contribute to neurologic damage, and whose levels can be modulated by endogenous factors including neurotransmitters such as norepinephrine (NE). We investigated the ability of NE to suppress microglial activation, in particular its effects on induction and activity of the inducible form of nitric oxide synthase (NOS2) and the possible role that IL-1β plays in that response.</p> <p>Methods</p> <p>Rat cortical microglia were stimulated with bacterial lipopolysaccharide (LPS) to induce NOS2 expression (assessed by nitrite and nitrate accumulation, NO production, and NOS2 mRNA levels) and IL-1β release (assessed by ELISA). Effects of NE were examined by co-incubating cells with different concentrations of NE, adrenergic receptor agonists and antagonists, cAMP analogs, and protein kinase (PK) A and adenylate cyclase (AC) inhibitors. Effects on the NFκB:IκB pathway were examined by using selective a NFκB inhibitor and measuring IκBα protein levels by western blots. A role for IL-1β in NOS2 induction was tested by examining effects of caspase-1 inhibitors and using caspase-1 deficient cells.</p> <p>Results</p> <p>LPS caused a time-dependent increase in NOS2 mRNA levels and NO production; which was blocked by a selective NFκB inhibitor. NE dose-dependently reduced NOS2 expression and NO generation, via activation of β2-adrenergic receptors (β2-ARs), and reduced loss of inhibitory IkBα protein. NE effects were replicated by dibutyryl-cyclic AMP. However, co-incubation with either PKA or AC inhibitors did not reverse suppressive effects of NE, but instead reduced nitrite production. A role for IL-1β was suggested since NE potently blocked microglial IL-1β production. However, incubation with a caspase-1 inhibitor, which reduced IL-1β levels, had no effect on NO production; incubation with IL-receptor antagonist had biphasic effects on nitrite production; and NE inhibited nitrite production in caspase-1 deficient microglia.</p> <p>Conclusions</p> <p>NE reduces microglial NOS2 expression and IL-1β production, however IL-1β does not play a critical role in NOS2 induction nor in mediating NE suppressive effects. Changes in magnitude or kinetics of cAMP may modulate NOS2 induction as well as suppression by NE. These results suggest that dysregulation of the central cathecolaminergic system may contribute to detrimental inflammatory responses and brain damage in neurological disease or trauma.</p>http://www.jneuroinflammation.com/content/1/1/9Nitric OxideNoradrenalineInterleukin-1βCytokinesCaspasecAMP |
| spellingShingle | Gavrilyuk Vitaliy Boullerne Anne I Dello Russo Cinzia Feinstein Douglas L Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1β production Journal of Neuroinflammation Nitric Oxide Noradrenaline Interleukin-1β Cytokines Caspase cAMP |
| title | Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1β production |
| title_full | Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1β production |
| title_fullStr | Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1β production |
| title_full_unstemmed | Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1β production |
| title_short | Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1β production |
| title_sort | inhibition of microglial inflammatory responses by norepinephrine effects on nitric oxide and interleukin 1β production |
| topic | Nitric Oxide Noradrenaline Interleukin-1β Cytokines Caspase cAMP |
| url | http://www.jneuroinflammation.com/content/1/1/9 |
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