Proinflammatory treatment of astrocytes with lipopolysaccharide results in augmented Ca2+ signaling through increased expression of via phospholipase A2 (iPLA2).

Abstract

Many Ca(2+)-regulated intracellular processes are involved in the development of neuroinflammation. However, the changes of Ca(2+) signaling in the brain under inflammatory conditions were hardly studied. ATP-induced Ca(2+) signaling is a central event of signal transmission in astrocytic networks. We investigated primary astrocytes after proinflammatory stimulation with lipopolysaccharide (LPS; 100 ng/ml) for 6-24 h. We reveal that Ca(2+) responses to purinergic ATP stimulation are significantly increased in amplitude and duration after stimulation with LPS. We detected that increased amplitudes of Ca(2+) responses to ATP in LPS-treated astrocytes can be explained by substantial increase of Ca(2+) load in stores in endoplasmic reticulum. The mechanism implies enhanced Ca(2+) store refilling due to the amplification of capacitative Ca(2+) entry. The reason for the increased duration of Ca(2+) responses in LPS-treated cells is also the amplified capacitative Ca(2+) entry. Next, we established that the molecular mechanism for the LPS-induced amplification of Ca(2+) responses in astrocytes is increased expression and activity of VIA phospholipase A(2) (VIA iPLA(2)). Indeed, both gene silencing with specific small interfering RNA and pharmacological inhibition of VIA iPLA(2) with S-bromoenol lactone reduced the load of the Ca(2+) stores and caused a decrease in the amplitudes of Ca(2+) responses in LPS-treated astrocytes to values, which were comparable with those in untreated cells. Our findings highlight a novel regulatory role of VIA iPLA(2) in development of inflammation in brain. We suggest that this enzyme might be a possible target for treatment of pathologies related to brain inflammation.

• Authors: Mikhail Strokin, Marina Sergeeva, Georg Reiser
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 300 Issue 3 Pg. C542-9 (Mar 2011) ISSN: 1522-1563 [Electronic] United States
• PMID: 21178110 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• Lipopolysaccharides
• Group VI Phospholipases A2
• Pla2g6 protein, rat
• Calcium

Topics

• Animals
• Animals, Newborn
• Astrocytes (enzymology)
• Calcium (physiology)
• Calcium Signaling (physiology)
• Cells, Cultured
• Endoplasmic Reticulum (metabolism, pathology)
• Gene Expression Regulation, Enzymologic (physiology)
• Gene Silencing (physiology)
• Gliosis (enzymology, pathology)
• Group VI Phospholipases A2 (antagonists & inhibitors, genetics, metabolism)
• Inflammation Mediators (pharmacology)
• Lipopolysaccharides (pharmacology)
• Rats
• Up-Regulation (genetics, physiology)