Phosphorylation of mitogen- and stress-activated protein kinase-1 in astrocytic inflammation: a possible role in inhibiting production of inflammatory cytokines.

Abstract

PURPOSE:

It is generally accepted that inflammation has a role in the progression of many central nervous system (CNS) diseases, although the mechanisms through which this occurs remain unclear. Among mitogen-activated protein kinase (MAPK) targets, mitogen- and stress-activated protein kinase (MSK1) has been thought to be involved in the pathology of inflammatory gene expression. In this study, the roles of MSK1 activation in neuroinflammation were investigated.

METHODS:

The bacterial lipopolysaccharide (LPS)-induced brain injury model was performed on Sprague-Dawley rats. The dynamic expression changes and the cellular location of p-MSK1 in the brain cortex were detected by Western blot and immunofluorescence staining. The synthesis of inflammatory cytokines in astrocytes was detected by enzyme-linked immunosorbent assay (ELISA).

RESULTS:

Phosphorylated MSK1 (p-MSK1 Thr-581) was induced significantly after intracerebral injection of LPS into the lateral ventricles of the rat brain. Specific upregulation of p-MSK1 in astrocytes was also observed in inflamed cerebral cortex. At 1 day after LPS stimulation, iNOS, TNFα expression, and the astrocyte marker glial fibrillary acidic protein (GFAP) were increased significantly. Also, in vitro studies indicated that the upregulation of p-MSK1 (Thr-581) may be involved in the subsequent astrocyte inflammatory process, following LPS challenge. Using an enzyme-linked immunosorbent assay (ELISA), it was confirmed that treatment with LPS in primary astrocytes stimulated the synthesis of inflammatory cytokines, through MAPKs signaling pathways. In cultured primary astrocytes, both knock-down of total MSK1 by small interfering RNAs (siRNA) or specific mutation of Thr-581 resulted in higher production of certain cytokines, such as TNFα and IL-6.

CONCLUSIONS:

Collectively, these results suggest that MSK1 phosphorylation is associated with the regulation of LPS-induced brain injury and possibly acts as a negative regulator of inflammation.

• Authors: Peipei Gong, Xide Xu, Jinlong Shi, Lanchun Ni, Qingfeng Huang, Liang Xia, Dekang Nie, Xiaojian Lu, Jian Chen, Wei Shi
• Journal: PloS one (PLoS One) Vol. 8 Issue 12 Pg. e81747 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24349124 (Publication Type: Journal Article)

Chemical References

• Glial Fibrillary Acidic Protein
• Interleukin-6
• Lipopolysaccharides
• RNA, Small Interfering
• Tumor Necrosis Factor-alpha
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Ribosomal Protein S6 Kinases, 90-kDa
• mitogen and stress-activated protein kinase 1

Topics

• Animals
• Astrocytes (metabolism, pathology)
• Brain Injuries (chemically induced, genetics, metabolism, pathology)
• Cerebral Cortex (metabolism, pathology)
• Gene Expression Regulation
• Glial Fibrillary Acidic Protein (genetics, metabolism)
• Inflammation (chemically induced, genetics, metabolism, pathology)
• Injections, Intraventricular
• Interleukin-6 (genetics, metabolism)
• Lipopolysaccharides
• Male
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Phosphorylation
• Primary Cell Culture
• RNA, Small Interfering (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Ribosomal Protein S6 Kinases, 90-kDa (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Tumor Necrosis Factor-alpha (genetics, metabolism)