Abstract
BackgroundSignal transducer and activator of transcription 3 (Stat3) is known to induce cell proliferation and inflammation by regulating gene transcription. Recent studies showed that Stat3 modulates nociceptive transmission by reducing spinal astrocyte proliferation. However, it is unclear whether Stat3 also contributes to the modulation of nociceptive transmission by regulating inflammatory response in spinal astrocytes. This study aimed at investigating the role of Stat3 on neuroinflammation during development of pain in rats after intrathecal injection of lipopolysaccharide (LPS).MethodsStat3 specific siRNA oligo and synthetic selective inhibitor (Stattic) were applied to block the activity of Stat3 in primary astrocytes or rat spinal cord, respectively. LPS was used to induce the expression of proinflammatory genes in all studies. Immunofluorescence staining of cells and slices of spinal cord was performed to monitor Stat3 activation. The impact of Stat3 inhibition on proinflammatory genes expression was determined by cytokine antibody array, enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Mechanical allodynia, as determined by the threshold pressure that could induce hind paw withdrawal after application of standardized von Frey filaments, was used to detect the effects of Stat3 inhibition after pain development with intrathecal LPS injection.ResultsIntrathecal injection of LPS activated Stat3 in reactive spinal astrocytes. Blockade of Stat3 activity attenuated mechanical allodynia significantly and was correlated with a lower number of reactive astrocytes in the spinal dorsal horn. In vitro study demonstrated that Stat3 modulated inflammatory response in primary astrocytes by transcriptional regulation of chemokine expression including Cx3cl1, Cxcl5, Cxcl10 and Ccl20. Similarly, inhibition of Stat3 reversed the expression of these chemokines in the spinal dorsal horn.ConclusionsStat3 acted as a transcriptional regulator of reactive astrocytes by modulating chemokine expression. Stat3 regulated inflammatory response in astrocytes and contributed to pain modulation. Blockade of Stat3 represents a new target for pain control.
Highlights
Signal transducer and activator of transcription 3 (Stat3) is a member of the Stat transcription factor family that regulates gene expression in response to extracellular signals
Stat3 acted as a transcriptional regulator of reactive astrocytes by modulating chemokine expression
Blockade of Stat3 represents a new target for pain control
Summary
Signal transducer and activator of transcription 3 (Stat3) is a member of the Stat transcription factor family that regulates gene expression in response to extracellular signals. Phosphorylated Stat regulates gene expression through binding to other transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells [2]. By regulating these target genes, Stat has been shown to increase cellular proliferation and augment inflammatory response [3]. Recent studies showed that Stat modulates nociceptive transmission by reducing spinal astrocyte proliferation It is unclear whether Stat contributes to the modulation of nociceptive transmission by regulating inflammatory response in spinal astrocytes. This study aimed at investigating the role of Stat on neuroinflammation during development of pain in rats after intrathecal injection of lipopolysaccharide (LPS)
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