PPAR-gamma regulation of IL-12 in CNS demyelination

Summary

Principal Investigator: John Bright
Affiliation: Clarian Health Partners
Country: USA
Abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that afflicts millions of young adults worldwide. Although the etiology is not known, the pathogenesis of MS appears to involve the breakdown of immune self-tolerance leading to inflammatory demyelinating attack on the CNS. Activation of macrophage/microglia, secretion of IL-12, differentiation of encephalitogenic Th1 cells and secretion of IFN gamma is critical events in CNS demyelination. Increased levels of IL-12 in the CNS associate with clinical disease in human and EAE animal model of MS. Inhibition of IL-12/IFN gamma axis prevents the development of EAE. Targeted expression of IL-12 in the CNS resulted spontaneous inflammation and demyelination in GF-IL-12 transgenic mice. PPAR gamma is a nuclear hormone receptor that regulates immune cell activation and inflammation. PPAR gamma agonists have been used for the treatment of diabetes and inflammatory diseases. Our preliminary studies suggested that PPAR gamma regulates IL-12/IFN gamma axis and CNS inflammation and demyelination in SJL/J mice. In this project, we propose to investigate the molecular mechanisms in PPAR gamma regulation of IL 12/IFN gamma axis in CNS demyelination. Using PPAR gamma agonists, 15d-PGJ2 and Ciglitazone, we will define the mechanisms in the PPAR gamma regulation of JAK-STAT and NF-kB signaling pathways leading to IL-12 gene expression in microglia and IFN gamma secretion in cells. Using GF-IL-12 transgenic mice we will define the mechanisms in the PPAR gamma regulation of IL-12 signaling leading to IFN gamma gene expression and Th1 differentiation in vitro and in vivo. Using GF-IL-12 transgenic and PPAR gamma heterozygous mice, we will define the role of PPAR gamma in the regulation of IL-12/IFN gamma axis in the pathogenesis of CNS inflammation and demyelination. We believe that this project is novel and will provide new insights on the mechanisms of PPAR gamma regulation of signaling pathways in IL-12/IFN gamma axis in Th1 differentiation in vitro and in CNS demyelination in vivo and new therapeutic agents for the treatment of human MS and other inflammatory autoimmune demyelinating diseases of the CNS.
Funding Period: 2002-12-15 - 2005-11-30
more information: NIH RePORT

Top Publications

  1. ncbi PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis
    Himanshu P Raikwar
    Department of Neurology, Vanderbilt University Medical Center, 1222 VSRH, 2201 Children s way, Nashville, TN 37212, USA
    J Neuroimmunol 167:99-107. 2005
  2. ncbi Curcumin induces growth-arrest and apoptosis in association with the inhibition of constitutively active JAK-STAT pathway in T cell leukemia
    Johnson Rajasingh
    Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
    Biochem Biophys Res Commun 340:359-68. 2006
  3. ncbi COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis
    Gladson Muthian
    Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    J Clin Immunol 26:73-85. 2006
  4. ncbi 1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis
    Gladson Muthian
    Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    J Neurosci Res 83:1299-309. 2006
  5. ncbi Setaria digitata secreted filarial lipids modulate IL-12 signaling through JAK-STAT pathway leading to the development of Th1 response
    Gladson Muthian
    Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
    Exp Parasitol 114:193-203. 2006
  6. ncbi 15-Deoxy-delta12,14-prostaglandin J2 regulates leukemia inhibitory factor signaling through JAK-STAT pathway in mouse embryonic stem cells
    Johnson Rajasingh
    Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
    Exp Cell Res 312:2538-46. 2006
  7. ncbi PPARgamma antagonists reverse the inhibition of neural antigen-specific Th1 response and experimental allergic encephalomyelitis by Ciglitazone and 15-deoxy-Delta12,14-prostaglandin J2
    Himanshu P Raikwar
    Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
    J Neuroimmunol 178:76-86. 2006
  8. doi 15-deoxy-Delta(12,14)-prostaglandin J(2) and curcumin modulate the expression of toll-like receptors 4 and 9 in autoimmune T lymphocyte
    Wanida Chearwae
    Neuroscience Research Laboratory, Methodist Research Institute at Clarian Health, 1800 North Capitol Avenue, Noyes Building E 504C, Indianapolis, IN 46202, USA
    J Clin Immunol 28:558-70. 2008
  9. pmc Stat4 isoforms differentially regulate inflammation and demyelination in experimental allergic encephalomyelitis
    Caiqing Mo
    Neuroscience Research Laboratory, Methodist Research Institute, Indianapolis, IN 46202, USA
    J Immunol 181:5681-90. 2008

Detail Information

Publications9

  1. ncbi PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis
    Himanshu P Raikwar
    Department of Neurology, Vanderbilt University Medical Center, 1222 VSRH, 2201 Children s way, Nashville, TN 37212, USA
    J Neuroimmunol 167:99-107. 2005
    ..These results further suggest that PPARgamma is a critical physiological regulator of CNS inflammation and demyelination in EAE...
  2. ncbi Curcumin induces growth-arrest and apoptosis in association with the inhibition of constitutively active JAK-STAT pathway in T cell leukemia
    Johnson Rajasingh
    Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
    Biochem Biophys Res Commun 340:359-68. 2006
    ..The induction of growth-arrest and apoptosis in association with the blockade of constitutively active JAK-STAT pathway suggests this be a mechanism by which curcumin induces antitumor activity in T cell leukemia...
  3. ncbi COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis
    Gladson Muthian
    Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    J Clin Immunol 26:73-85. 2006
    ....
  4. ncbi 1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis
    Gladson Muthian
    Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    J Neurosci Res 83:1299-309. 2006
    ....
  5. ncbi Setaria digitata secreted filarial lipids modulate IL-12 signaling through JAK-STAT pathway leading to the development of Th1 response
    Gladson Muthian
    Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
    Exp Parasitol 114:193-203. 2006
    ..These findings suggest that the SFL modulates Th1 immune response by blocking IL-12 signaling in T cells and thus play a role in host immune evasion of filarial parasites...
  6. ncbi 15-Deoxy-delta12,14-prostaglandin J2 regulates leukemia inhibitory factor signaling through JAK-STAT pathway in mouse embryonic stem cells
    Johnson Rajasingh
    Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
    Exp Cell Res 312:2538-46. 2006
    ..These results suggest that PPARgamma agonists regulate LIF signaling through JAK-STAT pathway leading to growth and self-renewal of ES cells...
  7. ncbi PPARgamma antagonists reverse the inhibition of neural antigen-specific Th1 response and experimental allergic encephalomyelitis by Ciglitazone and 15-deoxy-Delta12,14-prostaglandin J2
    Himanshu P Raikwar
    Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
    J Neuroimmunol 178:76-86. 2006
    ..These results suggest that Ciglitazone and 15d-PGJ2 ameliorate EAE through PPARgamma-dependent mechanisms and further confirm a physiological role for PPARgamma in the regulation of CNS inflammation and demyelination in EAE...
  8. doi 15-deoxy-Delta(12,14)-prostaglandin J(2) and curcumin modulate the expression of toll-like receptors 4 and 9 in autoimmune T lymphocyte
    Wanida Chearwae
    Neuroscience Research Laboratory, Methodist Research Institute at Clarian Health, 1800 North Capitol Avenue, Noyes Building E 504C, Indianapolis, IN 46202, USA
    J Clin Immunol 28:558-70. 2008
    ..T lymphocytes also express TLRs and function as costimulatory receptors to upregulate proliferation and cytokine production in response to specific agonists...
  9. pmc Stat4 isoforms differentially regulate inflammation and demyelination in experimental allergic encephalomyelitis
    Caiqing Mo
    Neuroscience Research Laboratory, Methodist Research Institute, Indianapolis, IN 46202, USA
    J Immunol 181:5681-90. 2008
    ..This study demonstrates that Stat4 isoforms differentially regulate inflammatory cytokines in association with distinct effects on the onset and severity of EAE...