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• W1987641831 abstract "Interleukin-12 (IL-12) is composed of two different subunits, p40 and p35. Expression of p40 mRNA but not that of p35 mRNA in excessive amount in the central nervous system of patients with multiple sclerosis (MS) suggests that IL-12 p40 may have a role in the pathogenesis of the disease. However, the mode of action of p40 is completely unknown. Because nitric oxide produced from the induction of nitric-oxide synthase (iNOS) also plays a vital role in the pathophysiology of MS, the present study was undertaken to explore the role of p40 in the induction of NO production and the expression of iNOS in microglia. Both IL-12 and p402, the p40 homodimer, dose-dependently induced the production of NO in BV-2 microglial cells. This induction of NO production was accompanied by an induction of iNOS protein and mRNA. Induction of NO production by the expression of mouse p40 cDNA but not that of the mouse p35 cDNA suggests that the p40 but not the p35 subunit of IL-12 is involved in the expression of iNOS. In addition to BV-2 glial cells, p402 also induced the production of NO in mouse primary microglia and peritoneal macrophages. However, both IL-12 and p402 were unable to induce the production of NO in mouse primary astrocytes. Because activation of NF-κB is important for the expression of iNOS, we investigated the effect of p402 on the activation of NF-κB. Induction of the DNA binding as well as the transcriptional activity of NF-κB by p402 and inhibition of p402-induced expression of iNOS by SN50, a cell-permeable peptide carrying the nuclear localization sequence of p50 NF-κB, but not by SN50M, a nonfunctional peptide mutant, suggests that p402 induces the expression of iNOS through the activation of NF-κB. This study delineates a novel role of IL-12 p40 in inducing the expression of iNOS in microglial cells, which may participate in the pathogenesis of neuroinflammatory diseases. Interleukin-12 (IL-12) is composed of two different subunits, p40 and p35. Expression of p40 mRNA but not that of p35 mRNA in excessive amount in the central nervous system of patients with multiple sclerosis (MS) suggests that IL-12 p40 may have a role in the pathogenesis of the disease. However, the mode of action of p40 is completely unknown. Because nitric oxide produced from the induction of nitric-oxide synthase (iNOS) also plays a vital role in the pathophysiology of MS, the present study was undertaken to explore the role of p40 in the induction of NO production and the expression of iNOS in microglia. Both IL-12 and p402, the p40 homodimer, dose-dependently induced the production of NO in BV-2 microglial cells. This induction of NO production was accompanied by an induction of iNOS protein and mRNA. Induction of NO production by the expression of mouse p40 cDNA but not that of the mouse p35 cDNA suggests that the p40 but not the p35 subunit of IL-12 is involved in the expression of iNOS. In addition to BV-2 glial cells, p402 also induced the production of NO in mouse primary microglia and peritoneal macrophages. However, both IL-12 and p402 were unable to induce the production of NO in mouse primary astrocytes. Because activation of NF-κB is important for the expression of iNOS, we investigated the effect of p402 on the activation of NF-κB. Induction of the DNA binding as well as the transcriptional activity of NF-κB by p402 and inhibition of p402-induced expression of iNOS by SN50, a cell-permeable peptide carrying the nuclear localization sequence of p50 NF-κB, but not by SN50M, a nonfunctional peptide mutant, suggests that p402 induces the expression of iNOS through the activation of NF-κB. This study delineates a novel role of IL-12 p40 in inducing the expression of iNOS in microglial cells, which may participate in the pathogenesis of neuroinflammatory diseases. inducible nitric-oxide synthase interleukin 12 Dulbecco's modified Eagle's medium lipopolysaccharide Nitric oxide (NO), derived in excessive amount from the activation of inducible nitric-oxide synthase (iNOS)1 in glial cells (microglia and astrocytes), is assumed to contribute to oligodendrocyte degeneration in demyelinating diseases and neuronal death during neurodegenerative diseases (1Galea E. Feinstein D.L. Reis D.J. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 10945-10949Crossref PubMed Scopus (465) Google Scholar, 2Koprowski H. Zheng Y.M. Heber-Katz E. Fraser N. Rorke L. Fu Z.F. Hanlon C. Dietzshold B. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3024-3027Crossref PubMed Scopus (470) Google Scholar, 3Mitrovic B. Ignarro L.J. Montestruque S. Smoll A. Merril J.E. Neurosci. 1994; 61: 575-585Crossref PubMed Scopus (246) Google Scholar, 4Bo L. Dawson T.M. Wesselingh S. Mork S. Choi S. Kong P.A. Hanley D. Trapp B.D. Ann. Neurol. 1994; 36: 778-786Crossref PubMed Scopus (550) Google Scholar, 5Merrill J.E. Ignarro L.J. Sherman M.P. Melinek J. Lane T.E. J. Immunol. 1993; 151: 2132-2141PubMed Google Scholar). Evidence from several laboratories emphasizes the involvement of NO in the pathophysiology of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), the animal model of MS (2Koprowski H. Zheng Y.M. Heber-Katz E. Fraser N. Rorke L. Fu Z.F. Hanlon C. Dietzshold B. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3024-3027Crossref PubMed Scopus (470) Google Scholar, 6Kolb H. Kolb-Bachofen V. Immunol. Today. 1992; 13: 157-160Abstract Full Text PDF PubMed Scopus (338) Google Scholar, 7McCatney-Francis N. Allen J.B. Mizel D.E. Albina J.E. Xie Q-W Nathan C.F. Wahl S.M. J. Ex. Med. 1993; 178: 749-754Crossref PubMed Scopus (594) Google Scholar). Analysis of CSF from MS patients has shown increased levels of nitrite and nitrate compared with normal control (9Johnson A.W. Land J.M. Thompson E.J. Bolanos J.P. Clark J.B. Heales S.J.R. J. Neurol. Neurosurg. Psychiatry. 1995; 58: 107-115Crossref PubMed Scopus (112) Google Scholar). The reaction of NO with O 2− forms peroxynitrite, ONOO−, a strong nitrosating agent capable of nitrosating tyrosine residues of a protein to nitrotyrosine. Increased levels of nitrotyrosine have been found in demyelinating lesions of MS brains as well as in spinal cords of mice with EAE (10Brenner T. Brocke S. Szafer F. Sobel R.A. Parkinson J.F. Perez D.H. Steinman L. J. Immunol. 1997; 158: 2940-2946PubMed Google Scholar, 11Hooper D.C. Scott G.S. Zborek A. Mikheeva T. Kean R.B. Koprowski H. Spitsin S.V. FASEB. J. 2000; 14: 691-698Crossref PubMed Scopus (315) Google Scholar). Subsequently, semiquantitative reverse transcriptase-polymerase chain reaction for iNOS mRNA in MS brains also shows markedly higher expression of iNOS mRNA in MS brains than in normal brains (12Brosan C.F. Battistini L. Raine C.S. Dickson D.W. Casadevall A. Lee S.C. Dev. Neurosci. 1994; 16: 152-161Crossref PubMed Scopus (205) Google Scholar, 4Bo L. Dawson T.M. Wesselingh S. Mork S. Choi S. Kong P.A. Hanley D. Trapp B.D. Ann. Neurol. 1994; 36: 778-786Crossref PubMed Scopus (550) Google Scholar).On the other hand, interleukin-12 (IL-12) plays a critical role in the early inflammatory response to infection and in the generation of T helper type 1 Th-1 cells, which favor cell-mediated immunity (14Hsieh C.S. Macatonia S.E. Tripp C.S. Wolf S.F. O'Garra A. Murphy K.M. Science. 1993; 260: 547-549Crossref PubMed Scopus (2861) Google Scholar). Recently, it has been found that overproduction of IL-12 can be dangerous to the host as it is involved in the pathogenesis of a number of autoimmune inflammatory diseases (e.g. multiple sclerosis, arthritis, insulin-dependent diabetes, Refs. 15Constantinescu C.S. Goodman D.B. Hilliard B. Wysocka M. Cohen J.A. Neurosci. Lett. 2000; 287: 171-174Crossref PubMed Scopus (34) Google Scholar,16Zipris D. Greiner D.L. Malkani S. Whalen B. Mordes J.P. Rossini A.A. J. Immunol. 1996; 156: 1315-1321PubMed Google Scholar). IL-12 consists of a heavy chain (p40) and a light chain (p35) linked covalently by disulfide bonds to give rise to a heterodimeric (p70) molecule (17Wolf S.F. Temple P.A. Kobayashi M. Young D. Dicig M. Lowe L. Dzialo R. Fitz L. Ferenz C. Hewick R.M. J. Immunol. 1991; 146: 3074-3081PubMed Google Scholar, 18Schoenhaut D.S. Chua A.O. et al.J. Immunol. 1992; 148: 3433-3440PubMed Google Scholar). It is known that the heterodimeric p70 molecule is the bioactive IL-12 cytokine, and both subunits must be coexpressed in the same cell to generate the bioactive form (19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar). However, the level of p40 is much higher than that of p35 in IL-12 producing cells (19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar). Again, several reports (15Constantinescu C.S. Goodman D.B. Hilliard B. Wysocka M. Cohen J.A. Neurosci. Lett. 2000; 287: 171-174Crossref PubMed Scopus (34) Google Scholar, 19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar, 20van Boxel-Dezaire A.H. Hoff S.C. et al.Ann. Neurol. 1999; 45: 695-703Crossref PubMed Scopus (242) Google Scholar, 21Fassbender K. Ragoschke A. Rossol S. Schwartz A. Mielke O. Paulig A. Hennerici M. Neurology. 1998; 51: 753-758Crossref PubMed Scopus (83) Google Scholar) indicate that the level of p40 mRNA in the central nervous system (CNS) of patients with MS is much higher than the CNS of control subjects whereas the level of p35 mRNA is about the same or decreases compared with controls. Similarly, in mice with experimental allergic encephalomyelitis (EAE), an animal model of MS, the expression of p40 mRNA but not that of p35 mRNA increases in brain and spinal cord (22Bright J.J. Musuro B.F. Du C. Sriram S. J. Neuroimmunol. 1998; 82: 22-30Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). However, the functional significance of marked overexpression of IL-12 p40 subunit in neural tissues of MS patients and EAE animals has not been delineated so far.We herein report the first evidence that p402, the IL-12 p40 homodimer, markedly induces the production of NO and the expression of iNOS through the activation of NF-κB in mouse microglia.DISCUSSIONIL-12, a heterodimeric cytokine, is most noted for its ability to regulate the balance between type 1 and type 2 helper T cells (14Hsieh C.S. Macatonia S.E. Tripp C.S. Wolf S.F. O'Garra A. Murphy K.M. Science. 1993; 260: 547-549Crossref PubMed Scopus (2861) Google Scholar, 19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar). Neither IL-12 subunits (p35 or p40) alone was found to display significant biological activity over a large range of concentrations (17Wolf S.F. Temple P.A. Kobayashi M. Young D. Dicig M. Lowe L. Dzialo R. Fitz L. Ferenz C. Hewick R.M. J. Immunol. 1991; 146: 3074-3081PubMed Google Scholar, 18Schoenhaut D.S. Chua A.O. et al.J. Immunol. 1992; 148: 3433-3440PubMed Google Scholar, 19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar). However, several lines of evidence indicate that p40 is expressed in excessive amount in the CNS of different demyelinating diseases such as multiple sclerosis (MS), Guillain-Barre syndrome, and animal models experimental autoimmune encephalomyelitis and neuritis (15Constantinescu C.S. Goodman D.B. Hilliard B. Wysocka M. Cohen J.A. Neurosci. Lett. 2000; 287: 171-174Crossref PubMed Scopus (34) Google Scholar, 16Zipris D. Greiner D.L. Malkani S. Whalen B. Mordes J.P. Rossini A.A. J. Immunol. 1996; 156: 1315-1321PubMed Google Scholar, 19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar, 20van Boxel-Dezaire A.H. Hoff S.C. et al.Ann. Neurol. 1999; 45: 695-703Crossref PubMed Scopus (242) Google Scholar, 21Fassbender K. Ragoschke A. Rossol S. Schwartz A. Mielke O. Paulig A. Hennerici M. Neurology. 1998; 51: 753-758Crossref PubMed Scopus (83) Google Scholar). On the other hand, the expression of p35 remains almost constant or decreased to some extent in the CNS of these demyelinating diseases compared with the CNS of control subjects (19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar, 20van Boxel-Dezaire A.H. Hoff S.C. et al.Ann. Neurol. 1999; 45: 695-703Crossref PubMed Scopus (242) Google Scholar, 21Fassbender K. Ragoschke A. Rossol S. Schwartz A. Mielke O. Paulig A. Hennerici M. Neurology. 1998; 51: 753-758Crossref PubMed Scopus (83) Google Scholar). However, the biological significance of this overexpression of p40 in the CNS of patients with demyelinating diseases is not known.Several lines of evidence presented in this manuscript clearly support the conclusion that IL-12 p40 homodimer, p402, induces the expression of iNOS in mouse microglia and macrophages. This conclusion was based on the following observations. First, p402induces the production of NO, which is inhibited by arginase, the enzyme which degrades the substrate of NOS, and by l-NMA, an inhibitor of NOS. Second, p402-mediated production of NO and expression of iNOS is inhibited by anti-mouse p40 but not by anti-mouse p70. Third, the expression of mouse p40 cDNA but not the mouse p35 cDNA induces the production of NO and the expression of iNOS, suggesting that the p40 but not the p35 subunit of IL-12 is involved in the induction of iNOS. Because NO produced from the activation of iNOS in the CNS participates in the pathophysiology of MS (4Bo L. Dawson T.M. Wesselingh S. Mork S. Choi S. Kong P.A. Hanley D. Trapp B.D. Ann. Neurol. 1994; 36: 778-786Crossref PubMed Scopus (550) Google Scholar, 6Kolb H. Kolb-Bachofen V. Immunol. Today. 1992; 13: 157-160Abstract Full Text PDF PubMed Scopus (338) Google Scholar, 7McCatney-Francis N. Allen J.B. Mizel D.E. Albina J.E. Xie Q-W Nathan C.F. Wahl S.M. J. Ex. Med. 1993; 178: 749-754Crossref PubMed Scopus (594) Google Scholar, 8Pahan K. Sheikh F.G. Namboodiri A.M.S. Singh I. J. Biol. Chem. 1998; 273: 12219-12226Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 9Johnson A.W. Land J.M. Thompson E.J. Bolanos J.P. Clark J.B. Heales S.J.R. J. Neurol. Neurosurg. Psychiatry. 1995; 58: 107-115Crossref PubMed Scopus (112) Google Scholar, 10Brenner T. Brocke S. Szafer F. Sobel R.A. Parkinson J.F. Perez D.H. Steinman L. J. Immunol. 1997; 158: 2940-2946PubMed Google Scholar, 11Hooper D.C. Scott G.S. Zborek A. Mikheeva T. Kean R.B. Koprowski H. Spitsin S.V. FASEB. J. 2000; 14: 691-698Crossref PubMed Scopus (315) Google Scholar, 12Brosan C.F. Battistini L. Raine C.S. Dickson D.W. Casadevall A. Lee S.C. Dev. Neurosci. 1994; 16: 152-161Crossref PubMed Scopus (205) Google Scholar), the overexpression of p40 mRNA in the CNS of MS patients (15Constantinescu C.S. Goodman D.B. Hilliard B. Wysocka M. Cohen J.A. Neurosci. Lett. 2000; 287: 171-174Crossref PubMed Scopus (34) Google Scholar, 19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar, 20van Boxel-Dezaire A.H. Hoff S.C. et al.Ann. Neurol. 1999; 45: 695-703Crossref PubMed Scopus (242) Google Scholar, 21Fassbender K. Ragoschke A. Rossol S. Schwartz A. Mielke O. Paulig A. Hennerici M. Neurology. 1998; 51: 753-758Crossref PubMed Scopus (83) Google Scholar) and the induction of iNOS by p40 suggest that p40 may participate in the pathophysiology of MS through the induction of iNOS.The level of p40 is much higher (5- to 500-fold) than that of the heterodimeric p70 in IL-12-producing cells (19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar). This excess p40 produced either in vitro in activated cells or in vivo in serum of endotoxin-treated mice exists as both dimer (20–40%) and monomer (the remainder, Ref. 19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar). Although the biological role of the monomeric as well as the dimeric form of p40 is not known, it has been suggested that p402 may act as a physiologic regulator of bioactive IL-12, because p402possesses IL-12 antagonist activity (19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar, 39Germann T. Rude E. Mattner F. Gately M.K. Immunol. Today. 1995; 16: 500-501Abstract Full Text PDF PubMed Scopus (31) Google Scholar). Therefore, the induction of iNOS by p402 suggests that p402 exhibits IL-12 antagonist activity possibly through the activation of iNOS. However, our observation that both p402 and the so-called bioactive IL-12 (heterodimeric p70) induce the production of NO and the expression of iNOS precludes this possibility. If iNOS-derived NO mediates the IL-12 antagonist activity of p402 then IL-12 itself can regulate its own function through the activation of iNOS. Apart from the IL-12 antagonist activity of p40, experiments onListeria monocytogenes infection in p40- and p35-deficient mice have shown that p40-deficient mice were susceptible to infection, but p35-deficient mice were able to eliminate bacteria despite the mouse's inability to produce biologically active heterodimeric IL-12 (19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar). Interestingly, it has also been found that the p35-deficient mouse produces normal levels of p40 (19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar). Taken together, these observations suggest that p40 alone may carry out some of the biological functions of heterodimeric IL-12. Here we present the first evidence that similar to IL-12, p402 can also induce the expression of iNOS and that iNOS-derived NO may account for the bacteria-eliminating property of both IL-12 and p40.The signaling events in cytokine-mediated induction of iNOS are not completely established so far. Proinflammatory cytokines (TNF-α, IL-1β, or IFN-γ) bind to their respective receptors and induce the expression of iNOS via NF-κB activation (26Pahan K. Liu X. Wood C. Raymond J.R. FEBS Lett. 2000; 472: 203-207Crossref PubMed Scopus (32) Google Scholar, 27Pahan K. Liu X. McKinney M.J. Wood C. Sheikh F.G. Raymond J.R. J. Neurochem. 2000; 74: 2288-2295Crossref PubMed Scopus (82) Google Scholar, 28Feinstein D.L. Galea E. Roberts S. Berquist H. Wang H. Reis D.J. J. Neurochem. 1994; 62: 315-321Crossref PubMed Scopus (150) Google Scholar, 29Pahan K. Namboodiri A.M.S. Sheikh F.G. Smith B.T. Singh I. J. Biol. 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McKinney M.J. Wood C. Sheikh F.G. Raymond J.R. J. Neurochem. 2000; 74: 2288-2295Crossref PubMed Scopus (82) Google Scholar, 28Feinstein D.L. Galea E. Roberts S. Berquist H. Wang H. Reis D.J. J. Neurochem. 1994; 62: 315-321Crossref PubMed Scopus (150) Google Scholar, 29Pahan K. Namboodiri A.M.S. Sheikh F.G. Smith B.T. Singh I. J. Biol. Chem. 1997; 272: 7786-7791Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 30Pahan K. Sheikh F.G. Khan M. Namboodiri A.M.S. Singh I. J. Biol. Chem. 1998; 273: 2591-2600Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 36Xie Q. Kashiwabara Y. Nathan C. J. Biol. Chem. 1994; 269: 4705-4708Abstract Full Text PDF PubMed Google Scholar, 37Pahan K. Sheikh F.G. Namboodiri A.M.S. Singh I. J. Clin. Invest. 1997; 100: 2671-2679Crossref PubMed Scopus (507) Google Scholar). 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Science. 1995; 267: 1485-1488Crossref PubMed Scopus (1310) Google Scholar) and binds to the consensus DNA-binding site present in the promoter region of iNOS.Our results have clearly shown that p402 induces the expression of iNOS through the activation of NF-κB. First, p402 induces the DNA-binding as well as the transcriptional activity of NF-κB. Second, expression of the mouse p40 cDNA but not the mouse p35 cDNA induces the activation of NF-κB and the expression of iNOS. Third, SN50, a cell-permeable peptide carrying the nuclear localization sequence of p50 NF-κB, but not mutant SN50 (SN50M) inhibits p402-mediated activation of NF-κB and expression of iNOS. It has been demonstrated that SN50 specifically blocks the nuclear translocation of NF-κB, but does not affect the activity of AP-1, SP-1 factor, and OCT-1 transcriptional factors (48Qin Z.H. Wang Y. Nakai M. Chase T.N. Mol. Pharmacol. 1998; 53: 33-42Crossref PubMed Scopus (164) Google Scholar) suggesting that SN50 inhibits the expression of iNOS in p402-stimulated microglial cells by inhibiting the activation of NF-κB. In addition, these results also suggest that IL-12 p402 is biologically active and that p402alone can activate microglial cells.At present, it is unclear how p402 activates NF-κB and induces iNOS in microglial cells. IL-12 p402 has been shown to antagonize bioactive IL-12 heterodimer by binding to the IL-12 receptor complex (19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar). The high affinity IL-12 receptor is composed of a low affinity IL-12Rβ1 combined with a low affinity IL-12Rβ2, which are responsible for Tyk2/Jak2 activation, respectively, and STAT4 activation (19Gately M.K. Renzetti L.M. Magram J. Stern A.S. Adorini L. Gubler U. Presky D.H. Annu. Rev. Immunol. 1998; 16: 495-521Crossref PubMed Scopus (1090) Google Scholar, 49Wang X. Wilkinson V.L. Podlaski F.J. Wu C. Stern A.S. Presky D.H. Magram J. Eur. J. Immunol. 1999; 29: 2007-2013Crossref PubMed Scopus (47) Google Scholar). It appears that p402 binds to IL-12Rβ1 rather than IL-12Rβ2, whereas bioactive IL-12 binds the receptor complex with high affinity (50Presky D.H. Yang H. Minetti L.J. Chua A.O. Nabavi N. Wu C.Y. Gately M.K. Gubler U. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14002-14007Crossref PubMed Scopus (574) Google Scholar). Therefore, it is possible that p402 activates NF-κB and induces the expression of iNOS through the IL-12Rβ1.NO, a diffusible free radical, plays many roles as a signaling and as a effector molecule in diverse biological systems including neuronal messenger, vasodilation, and antimicrobial and antitumor activities (51Nathan C. FASEB. J. 1992; 6: 3051-3064Crossref PubMed Scopus (4133) Google Scholar, 52Jaffrey S.R. Snyder S.H. Annu. Rev. Cell Dev. Biol. 1995; 11: 417-440Crossref PubMed Scopus (304) Google Scholar). In the nervous system the NO appears to have both neurotoxic and neuroprotective effects and may have a role in the pathogenesis of stroke and other neurodegenerative diseases and in demyelinating conditions (e.g. multiple sclerosis, experimental allergic encephalopathy, X-adrenoleukodystrophy) associated with infiltrating macrophages and the production of proinflammatory cytokines (53Dawson V.L. Dawson T.M. London E.D. Bredt D.T. Snyder S.H. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 6368-6371Crossref PubMed Scopus (2098) Google Scholar). NO and peroxynitrite (reaction product of NO and O 2−) are potentially toxic molecules to neurons and oligodendrocytes that may mediate toxicity through the formation of iron-NO complexes of iron containing enzyme systems (54Drapier J-C. Hibbs J.B. J. Immunol. 1988; 140: 2829-2838PubMed Google Scholar), oxidation of protein sulfhydryl groups (55Radi R. Beckman J.S. Bush K.M. Freeman B.A. J. Biol. Chem. 1991; 266: 4244-4250Abstract Full Text PDF PubMed Google Scholar), nitration of proteins, and nitrosylation of nucleic acids and DNA strand breaks (56Wink D.A. Kasprazak K.S. et al.Science. 1991; 254: 1001-1003Crossref PubMed Scopus (1124) Google Scholar). Although monocytes/macrophages are the primary source of iNOS in inflammation, LPS and proinflammatory cytokines induce a similar response in microglia (35Suzumura A. Sawada M. Takayanagi T. Brain Res. 1998; 787: 139-142Crossref PubMed Scopus (51) Google Scholar, 8Pahan K. Sheikh F.G. Namboodiri A.M.S. Singh I. J. Biol. Chem. 1998; 273: 12219-12226Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 13Hu S.X. Sheng W.S. Peterson P.K. Chao C.C. Glia. 1995; 15: 491-494Crossref PubMed Scopus (82) Google Scholar). NO derived from microglia has also been implicated in the damage of myelin-producing oligodendrocytes in demyelinating disorders like multiple sclerosis and neuronal death during Alzheimer's disease and brain trauma (2Koprowski H. Zheng Y.M. Heber-Katz E. Fraser N. Rorke L. Fu Z.F. Hanlon C. Dietzshold B. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3024-3027Crossref PubMed Scopus (470) Google Scholar, 3Mitrovic B. Ignarro L.J. Montestruque S. Smoll A. Merril J.E. Neurosci. 1994; 61: 575-585Crossref PubMed Scopus (246) Google Scholar, 4Bo L. Dawson T.M. Wesselingh S. Mork S. Choi S. Kong P.A. Hanley D. Trapp B.D. Ann. Neurol. 1994; 36: 778-786Crossref PubMed Scopus (550) Google Scholar, 5Merrill J.E. Ignarro L.J. Sherman M.P. Melinek J. Lane T.E. J. 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Merril J.E. Neurosci. 1994; 61: 575-585Crossref PubMed Scopus (246) Google Scholar, 4Bo L. Dawson T.M. Wesselingh S. Mork S. Choi S. Kong P.A. Hanley D. Trapp B.D. Ann. Neurol. 1994; 36: 778-786Crossref PubMed Scopus (550) Google Scholar, 5Merrill J.E. Ignarro L.J. Sherman M.P. Melinek J. Lane T.E. J. Immunol. 1993; 151: 2132-2141PubMed Google Scholar). Evidence from several laboratories emphasizes the involvement of NO in the pathophysiology of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), the animal model of MS (2Koprowski H. Zheng Y.M. Heber-Katz E. Fraser N. Rorke L. Fu Z.F. Hanlon C. Dietzshold B. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3024-3027Crossref PubMed Scopus (470) Google Scholar, 6Kolb H. Kolb-Bachofen V. Immunol. Today. 1992; 13: 157-160Abstra" @default.
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