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Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis.

Bhasin M, Wu M, Tsirka SE - BMC Immunol. (2007)

Bottom Line: Myelin Oligodendrocyte Glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is the most commonly used mouse model for multiple sclerosis (MS).Microglial activation is mediated by the extracellular protease tissue Plasminogen Activator (tPA), and mice lacking tPA display altered EAE progression.Specific molecular targets have been identified that represent potential avenues of exploration for the treatment and prevention of MS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genetics, Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA. bhasin@pharm.stonybrook.edu <bhasin@pharm.stonybrook.edu>

ABSTRACT

Background: Myelin Oligodendrocyte Glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is the most commonly used mouse model for multiple sclerosis (MS). During the of progression of EAE, microglia, the immunocompetent cells of the brain, become activated and accumulate around demyelinated lesions. Microglial activation is mediated by the extracellular protease tissue Plasminogen Activator (tPA), and mice lacking tPA display altered EAE progression. In this study, we have used pharmacological inhibitors and stimulators of microglial/macrophage activation to examine the temporal requirement for microglial activation in EAE progression and to determine whether such approaches might potentially be of therapeutic value.

Results: Intervention using the tripeptide macrophage/microglia inhibitory factor MIF (TKP) and the tetrapeptide macrophage/microglial stimulator tuftsin (TKPR) attenuated EAE symptoms and revealed that the timing of macrophage/microglial activation is critical for the clinical outcome of EAE. We show that the disease progression can potentially be manipulated favorably at early stages by altering the timing of microglial activation, which in turn alters the systemic immune response to favor upregulation of T helper cell 2 genes that promote recovery from EAE.

Conclusion: Preventative and therapeutic modulation of macrophage/microglial activity significantly alters the outcome of EAE at symptomatic stages. Specific molecular targets have been identified that represent potential avenues of exploration for the treatment and prevention of MS.

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Related in: MedlinePlus

Quantification of T-bet (Th1 transcription factor) and GATA-3 (Th2 transcription factor) expression. Real time RT-PCR was performed on RNA from spinal cord homogenates extracted after the different treatments with MIF and tuftsin at various timepoints. Expression levels obtained for T-bet and GATA-3 were normalized against actin levels at the same timepoint in the same sample. #, denotes significant differences between the two (p < 0.05) groups for the specific treatment and timepoint.
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Figure 7: Quantification of T-bet (Th1 transcription factor) and GATA-3 (Th2 transcription factor) expression. Real time RT-PCR was performed on RNA from spinal cord homogenates extracted after the different treatments with MIF and tuftsin at various timepoints. Expression levels obtained for T-bet and GATA-3 were normalized against actin levels at the same timepoint in the same sample. #, denotes significant differences between the two (p < 0.05) groups for the specific treatment and timepoint.

Mentions: Differential expression of the transcription factors T-bet and GATA-3 were used to analyze the Th1/Th2 balance in EAE mice in all conditions, since T-bet controls the transcription of Th1 markers and GATA-3 drives transcription of Th2 markers. PBS-treated, MOG-injected wt and tPA-/- mice were characterized by a strong Th1 response, indicated by increasing levels of T-bet expression, and lowered levels of GATA-3. This result is in agreement with reports indicating that EAE is primarily a Th1-mediated disease [34]. However, both MIF and tuftsin administration into MOG-injected wt mice resulted in a shift towards increased GATA-3 expression, indicating a switch to a Th2 response. Similarly, the infusion of tuftsin in tPA-/- mice resulted in a strong Th2 response (Fig 7). These results were further corroborated by measuring the expression levels of Th1- (TNFalpha) and Th2- (IL10) specific cytokines by RT-PCR and ELISA in spinal cord extracts (data not shown).


Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis.

Bhasin M, Wu M, Tsirka SE - BMC Immunol. (2007)

Quantification of T-bet (Th1 transcription factor) and GATA-3 (Th2 transcription factor) expression. Real time RT-PCR was performed on RNA from spinal cord homogenates extracted after the different treatments with MIF and tuftsin at various timepoints. Expression levels obtained for T-bet and GATA-3 were normalized against actin levels at the same timepoint in the same sample. #, denotes significant differences between the two (p < 0.05) groups for the specific treatment and timepoint.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1937009&req=5

Figure 7: Quantification of T-bet (Th1 transcription factor) and GATA-3 (Th2 transcription factor) expression. Real time RT-PCR was performed on RNA from spinal cord homogenates extracted after the different treatments with MIF and tuftsin at various timepoints. Expression levels obtained for T-bet and GATA-3 were normalized against actin levels at the same timepoint in the same sample. #, denotes significant differences between the two (p < 0.05) groups for the specific treatment and timepoint.
Mentions: Differential expression of the transcription factors T-bet and GATA-3 were used to analyze the Th1/Th2 balance in EAE mice in all conditions, since T-bet controls the transcription of Th1 markers and GATA-3 drives transcription of Th2 markers. PBS-treated, MOG-injected wt and tPA-/- mice were characterized by a strong Th1 response, indicated by increasing levels of T-bet expression, and lowered levels of GATA-3. This result is in agreement with reports indicating that EAE is primarily a Th1-mediated disease [34]. However, both MIF and tuftsin administration into MOG-injected wt mice resulted in a shift towards increased GATA-3 expression, indicating a switch to a Th2 response. Similarly, the infusion of tuftsin in tPA-/- mice resulted in a strong Th2 response (Fig 7). These results were further corroborated by measuring the expression levels of Th1- (TNFalpha) and Th2- (IL10) specific cytokines by RT-PCR and ELISA in spinal cord extracts (data not shown).

Bottom Line: Myelin Oligodendrocyte Glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is the most commonly used mouse model for multiple sclerosis (MS).Microglial activation is mediated by the extracellular protease tissue Plasminogen Activator (tPA), and mice lacking tPA display altered EAE progression.Specific molecular targets have been identified that represent potential avenues of exploration for the treatment and prevention of MS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genetics, Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA. bhasin@pharm.stonybrook.edu <bhasin@pharm.stonybrook.edu>

ABSTRACT

Background: Myelin Oligodendrocyte Glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is the most commonly used mouse model for multiple sclerosis (MS). During the of progression of EAE, microglia, the immunocompetent cells of the brain, become activated and accumulate around demyelinated lesions. Microglial activation is mediated by the extracellular protease tissue Plasminogen Activator (tPA), and mice lacking tPA display altered EAE progression. In this study, we have used pharmacological inhibitors and stimulators of microglial/macrophage activation to examine the temporal requirement for microglial activation in EAE progression and to determine whether such approaches might potentially be of therapeutic value.

Results: Intervention using the tripeptide macrophage/microglia inhibitory factor MIF (TKP) and the tetrapeptide macrophage/microglial stimulator tuftsin (TKPR) attenuated EAE symptoms and revealed that the timing of macrophage/microglial activation is critical for the clinical outcome of EAE. We show that the disease progression can potentially be manipulated favorably at early stages by altering the timing of microglial activation, which in turn alters the systemic immune response to favor upregulation of T helper cell 2 genes that promote recovery from EAE.

Conclusion: Preventative and therapeutic modulation of macrophage/microglial activity significantly alters the outcome of EAE at symptomatic stages. Specific molecular targets have been identified that represent potential avenues of exploration for the treatment and prevention of MS.

Show MeSH
Related in: MedlinePlus