Experimental allergic encephalomyelitis (EAE) is an animal model for Multiple Sclerosis (MS), the most common human demyelinating disease of the CNS of unknown etiology. In spite of extensive research to develop pharmacotherapeutic agents to inhibit neurologic disability in MS, no effective therapy is available to halt this disease process. In both EAE and MS, demyelination is associated with a broad-spectrum inflammatory reaction. Expression of most of the inflammatory molecules is controlled by NF-kappaB. We have discovered a new group of inducers of NF-kappaB activation [interleukin-12 (IL-12) p40 homodimer (p40-2) and monomer (p40)] in glial cells. It was known that p40-2 and p40 were biologically inactive. However, we have found that both p40-2 and p40 markedly induce the activation of NF-kappaB and the expression of NF-kappaB dependent proinflammatory genes in microglial cells. Therefore, understanding how and by which mechanisms these cytokines alter the inflammatory response in EAE is important for the better understanding of the pathogenesis of inflammatory demyelination including MS. In this grant application, studies have been proposed from various angles to reveal physiological and pathophysiological functions for p40-2 and p40. First, we will generate monoclonal antibodies against p40-2 and p40. Second, we will study the role of p40-2 and p40 in modulating the ability of MBP-specific T cells to differentiate into either Th1 or Th2 type using recombinant proteins as well as monoclonal antibodies. Third, we will delineate the effect of p40-2 and p40 on encephalitogenicity of MBP-specific T cells. This will be substantiated by identifying levels of perivascular cuffing, proinflammatory molecules and myelin-specific genes in spinal cord of EAE mice. Fourth, we will investigate the role of IL-12Rb1 and IL-12Rb2 in p40-2 - and p40-induced expression of proinflammatory molecules and transcription factors in microglia and macrophages using knock out mice and siRNA approach. In summary, the results obtained from this proposal will characterize molecular mechanisms for novel biological functions of p40-2 and p40 and delineate their role in the neuroinflammatory disease process of EAE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039940-10
Application #
7534985
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Utz, Ursula
Project Start
2000-04-01
Project End
2011-11-30
Budget Start
2008-12-01
Budget End
2011-11-30
Support Year
10
Fiscal Year
2009
Total Cost
$292,063
Indirect Cost
Name
Rush University Medical Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Mondal, Susanta; Brahmachari, Saurav; Pahan, Kalipada (2012) Regulation of encephalitogenicity of neuroantigen-primed T cells by nitric oxide: Implications for multiple sclerosis. J Clin Cell Immunol 3:124
Pahan, Kalipada (2011) Immunomodulation of experimental allergic encephalomyelitis by cinnamon metabolite sodium benzoate. Immunopharmacol Immunotoxicol 33:586-93
Roy, Avik; Pahan, Kalipada (2011) Prospects of statins in Parkinson disease. Neuroscientist 17:244-55
Brahmachari, Saurav; Pahan, Kalipada (2010) Gender-specific expression of beta1 integrin of VLA-4 in myelin basic protein-primed T cells: implications for gender bias in multiple sclerosis. J Immunol 184:6103-13
Brahmachari, Saurav; Pahan, Kalipada (2010) Myelin basic protein priming reduces the expression of Foxp3 in T cells via nitric oxide. J Immunol 184:1799-809
Jana, Arundhati; Pahan, Kalipada (2010) Sphingolipids in multiple sclerosis. Neuromolecular Med 12:351-61
Jana, Arundhati; Pahan, Kalipada (2010) Fibrillar amyloid-beta-activated human astroglia kill primary human neurons via neutral sphingomyelinase: implications for Alzheimer's disease. J Neurosci 30:12676-89
Pahan, Kalipada (2010) Neuroimmune pharmacological control of EAE. J Neuroimmune Pharmacol 5:165-7
Jana, Malabendu; Pahan, Kalipada (2009) Induction of lymphotoxin-alpha by interleukin-12 p40 homodimer, the so-called biologically inactive molecule, but not IL-12 p70. Immunology 127:312-25
Brahmachari, Saurav; Jana, Arundhati; Pahan, Kalipada (2009) Sodium benzoate, a metabolite of cinnamon and a food additive, reduces microglial and astroglial inflammatory responses. J Immunol 183:5917-27

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