Reactive Gliosis as a Consequence of Interleukin-6 Expression in the Brain: Studies in Transgenic Mice

Chiang, Chi-Shiun; Stalder, A.; Samimi, Ana; Campbell, Iain L.

doi:10.1159/000112109

Cited by 227 publications

(158 citation statements)

References 52 publications

Supporting

Mentioning

134

Contrasting

Unclassified

Order By: Relevance

“…Degeneration of severed axon tracts appears to lead to gliosis, even in regions remote from the site of trauma in the brain or spinal cord (Barrett et al, 1981;Fitch and Silver, 1997a;Massey, et al, 2006;Murray et al, 1990;Steward and Trimmer, 1997). Cytokines or other molecules that may trigger gliosis include TNF-alpha (Rostworowski et al, 1997), endothelin-1 (Hama et al, 1997), IL-1 (Giulian and Lachman, 1985), IL-6 (Chiang et al, 1994), thrombin (Nishino et al, 1993), and CNTF (Kahn et al, 1995). Some of these may originate as soluble serum factors, or they can be directly produced by astrocytes, activated microglia, or peripheral macrophages.…”

Section: Triggers For the Production Of Inhibitory Extracellular Matrixmentioning

confidence: 99%

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

Fitch

Silver

2008

Experimental Neurology

865

657

View full text Add to dashboard Cite

Spinal cord and brain injuries lead to complex cellular and molecular interactions within the central nervous system in an attempt to repair the initial tissue damage. Many studies have illustrated the importance of the glial cell response to injury, and the influences of inflammation and wound healing processes on the overall morbidity and permanent disability that result. The abortive attempts of neuronal regeneration after spinal cord injury are influenced by inflammatory cell activation, reactive astrogliosis and the production of both growth promoting and inhibitory extracellular molecules. Despite the historical perspective that the glial scar was a mechanical barrier to regeneration, inhibitory molecules in the forming scar and methods to overcome them have suggested molecular modification strategies to allow neuronal growth and functional regeneration. Unlike myelin associated inhibitory molecules, which remain at largely static levels before and after central nervous system trauma, inhibitory extracellular matrix molecules are dramatically upregulated during the inflammatory stages after injury providing a window of opportunity for the delivery of candidate therapeutic interventions. While high dose methylprednisolone steroid therapy alone has not proved to be the solution to this difficult clinical problem, other strategies for modulating inflammation and changing the make up of inhibitory molecules in the extracellular matrix are providing robust evidence that rehabilitation after spinal cord and brain injury has the potential to significantly change the outcome for what was once thought to be permanent disability.

show abstract

Section: Triggers For the Production Of Inhibitory Extracellular Matrixmentioning

confidence: 99%

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

Fitch

Silver

2008

Experimental Neurology

865

657

View full text Add to dashboard Cite

show abstract

“…M88242) was synthesized by RT-PCR using mouse brain RNA as a template and cloned into pGEM-4. Fragments of the RPL32-4A gene (31) and the inducible NO synthase (iNOS) gene (32) were also cloned into pGEM-4. L32 served as an internal loading control.…”

Section: Rnase Protection Assaymentioning

confidence: 99%

IL-10 Is a Central Regulator of Cyclooxygenase-2 Expression and Prostaglandin Production

Berg

Zhang

Lauricella

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

IL-10 is a potent anti-inflammatory and immune regulatory cytokine. IL-10−/− mice produce exaggerated amounts of inflammatory cytokines when stimulated with LPS, indicating that endogenous IL-10 is a central regulator of inflammatory cytokine production in vivo. PGs are lipid mediators that are also produced in large amounts during the inflammatory response. To study the role of IL-10 in the regulation of PG production during the acute inflammatory response, we evaluated LPS-induced cyclooxygenase (COX) expression and PG production in wild-type (wt) and IL-10−/− mice. LPS-induced PGE2 production from IL-10−/− spleen cells was 5.6-fold greater than that from wt spleen cells. LPS stimulation resulted in the induction of COX-2 mRNA and protein in both wt and IL-10−/− spleen cells; however, the magnitude of increase in COX-2 mRNA was 5.5-fold greater in IL-10−/− mice as compared with wt mice. COX-1 protein levels were not affected by LPS stimulation in either wt or IL-10−/− mice. Neutralization of IFN-γ, TNF-α, or IL-12 markedly decreased the induction of COX-2 in IL-10−/− spleen cells, suggesting that increased inflammatory cytokine production mediates much of the COX-2 induction in IL-10−/− mice. Treatment of IL-10−/− mice with low doses of LPS resulted in a marked induction of COX-2 mRNA in the spleen, whereas wt mice had minimal expression of COX-2 mRNA. These findings indicate that, in addition to IL-10’s central role in the regulation of inflammatory cytokines, endogenous IL-10 is an important regulator of PG production in the response to LPS.

show abstract

“…Such alterations could presumably make an important contribution to the clinicopathological features of many neurological disorders, but the possibility that they are simply the consequence and not the cause must be ruled out experimentally. Results obtained in transgenic mice with astrocyte-targeted expression of cytokines such as IL-6 (5,6,8,12,14,31,52,60), IL-3 (13), IFN-␣ (1), and TNF-␣ (59) have unequivocally demonstrated that an abnormal cytokine production has the potential to cause devastating neurological disorders. Interestingly, each of these cytokines caused a specific repertoire of clinicopathological sequelae that presumably reflect the unique actions of the particular cytokine expressed.…”

Section: Introductionmentioning

confidence: 99%

Metallothioneins Are Upregulated in Symptomatic Mice with Astrocyte-Targeted Expression of Tumor Necrosis Factor-α

Carrasco

Giralt

Penkowa

et al. 2000

Experimental Neurology

Self Cite

View full text Add to dashboard Cite

Transgenic mice expressing TNF-␣ under the regulatory control of the GFAP gene promoter (GFAP-TNF␣ mice) exhibit a unique, late-onset chronic-progressive neurological disorder with meningoencephalomyelitis, neurodegeneration, and demyelination with paralysis. Here we show that the metallothionein-I ؉ II (MT-I ؉ II) isoforms were dramatically upregulated in the brain of symptomatic but not presymptomatic GFAP-TNF␣ mice despite TNF-␣ expression being present in both cases. In situ hybridization analysis for MT-I RNA and radioimmunoassay results for MT-I ؉ II protein revealed that the induction was observed in the cerebellum but not in other brain areas. Increased MT-I RNA levels occurred in the Purkinje and granular neuronal layers of the cerebellum but also in the molecular layer. Reactive astrocytes, activated rod-like microglia, and macrophages, but not the infiltrating lymphocytes, were identified as the cellular sources of the MT-I ؉ II proteins. In situ hybridization for MT-III RNA revealed a modest increase in the white matter of the cerebellum, which was confirmed by immunocytochemistry. MT-III immunoreactivity was present in cells which were mainly round or amoeboid monocytes/macrophages. The pattern of expression of the different MT isoforms in the GFAP-TNF␣ mice differed substantially from that described previously in GFAP-IL6 mice, demonstrating unique effects associated with the expression of each cytokine. The results suggest that the MT expression in the CNS reflects the inflammatory response and associated damage rather than a direct role of the TNF-␣ in their regulation and support a major role of these proteins during CNS injury.

show abstract

Reactive Gliosis as a Consequence of Interleukin-6 Expression in the Brain: Studies in Transgenic Mice

Cited by 227 publications

References 52 publications

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

IL-10 Is a Central Regulator of Cyclooxygenase-2 Expression and Prostaglandin Production

Metallothioneins Are Upregulated in Symptomatic Mice with Astrocyte-Targeted Expression of Tumor Necrosis Factor-α

Contact Info

Product

Resources

About