{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T10:37:54Z","timestamp":1775644674014,"version":"3.50.1"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2009,8,1]],"date-time":"2009-08-01T00:00:00Z","timestamp":1249084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Regulatory T cells (Tregs) play a pivotal role in the maintenance of homeostasis between immune response and immune tolerance. The transcription factor Foxp3 and the surface protein CD25 are the two key molecules characterizing Tregs. In autoimmune and various other chronic inflammatory diseases, the expression of Foxp3 is severely down-regulated. However, the molecular mechanism underlying the down-regulation of Foxp3 is not understood yet. Because the IL-12p40 homodimer (p402) is markedly up-regulated in response to various inflammatory stimuli, the present study was undertaken to explore the role of p402 in the regulation of Foxp3 in naive mouse splenocytes. IL-12p402 dose-dependently inhibited the expression of Foxp3 and CD25, but not CD4. Interestingly, this inhibition was absent in splenocytes of IL-12R\u03b21\u2212\/\u2212, but not IL-12R\u03b22\u2212\/\u2212, mice. Moreover, suppression of Foxp3 in wild-type and IL-12R\u03b22\u2212\/\u2212 splenocytes was accompanied by production of NO. Consistently, l-N6-(1-iminoethyl)-lysine hydrochloride, an inhibitor of inducible NO synthase (iNOS), and PTIO, a scavenger of NO, restored the expression of Foxp3 and CD25 in p402-stimulated splenocytes, and p402 was unable to down-regulate Foxp3 and CD25 in splenocytes from iNOS\u2212\/\u2212 mice. Furthermore, NO, but not p402, was able to inhibit Foxp3 in purified CD4+CD25+ T cells in the absence of iNOS-expressing cells. Hence, our results clearly demonstrate that p402 induces NO production via IL-12R\u03b21 and that NO subsequently suppresses Tregs in naive mouse splenocytes. This study, therefore, delineates an unprecedented biological function of p402 in the regulation of Foxp3 via IL-12R\u03b21-mediated NO production.<\/jats:p>","DOI":"10.4049\/jimmunol.0800276","type":"journal-article","created":{"date-parts":[[2009,7,9]],"date-time":"2009-07-09T00:36:40Z","timestamp":1247099800000},"page":"2045-2058","source":"Crossref","is-referenced-by-count":55,"title":["Suppression of Regulatory T Cells by IL-12p40 Homodimer via Nitric Oxide"],"prefix":"10.1093","volume":"183","author":[{"given":"Saurav","family":"Brahmachari","sequence":"first","affiliation":[{"name":"Department of Neurological Sciences, Rush University Medical Center , Chicago, IL 60612"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kalipada","family":"Pahan","sequence":"additional","affiliation":[{"name":"Department of Neurological Sciences, Rush University Medical Center , Chicago, IL 60612"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,8,1]]},"reference":[{"key":"2025032619371449300_R1","first-page":"495","article-title":"The interleukin-12\/interleukin-12-receptor system: role in normal and pathologic immune responses.","volume-title":"Annu. Rev. Immunol.","year":"1998"},{"key":"2025032619371449300_R2","first-page":"471","article-title":"IL-12-deficient mice are defective in IFN \u03b3 production and type 1 cytokine responses.","volume-title":"Immunity","year":"1996"},{"key":"2025032619371449300_R3","first-page":"1553","article-title":"Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response.","volume-title":"Eur. J. Immunol.","year":"1996"},{"key":"2025032619371449300_R4","first-page":"1261","article-title":"Inducible nitric oxide is essential for host control of persistent but not acute infection with the intracellular pathogen Toxoplasma gondii.","volume-title":"J. Exp. Med.","year":"1997"},{"key":"2025032619371449300_R5","first-page":"39","article-title":"Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis.","volume-title":"J. Exp. Med.","year":"1997"},{"key":"2025032619371449300_R6","first-page":"3074","article-title":"Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells.","volume-title":"J. Immunol.","year":"1991"},{"key":"2025032619371449300_R7","first-page":"171","article-title":"Murine macrophages stimulated with central and peripheral nervous system myelin or purified myelin proteins release inflammatory products.","volume-title":"Neurosci. Lett.","year":"2000"},{"key":"2025032619371449300_R8","first-page":"695","article-title":"Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis.","volume-title":"Ann. Neurol.","year":"1999"},{"key":"2025032619371449300_R9","first-page":"753","article-title":"Increased release of interleukin-12p40 in MS: association with intracerebral inflammation.","volume-title":"Neurology","year":"1998"},{"key":"2025032619371449300_R10","first-page":"230","article-title":"Molecular characterization of interleukin 12.","volume-title":"Arch. Biochem. Biophys.","year":"1992"},{"key":"2025032619371449300_R11","first-page":"1387","article-title":"Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells.","volume-title":"J. Exp. Med.","year":"1992"},{"key":"2025032619371449300_R12","first-page":"4381","article-title":"In vivo production and function of IL-12 p40 homodimers.","volume-title":"J. Immunol.","year":"1997"},{"key":"2025032619371449300_R13","first-page":"7899","article-title":"Induction of nitric-oxide synthase and activation of NF-\u03baB by interleukin-12 p40 in microglial cells.","volume-title":"J. Biol. Chem.","year":"2001"},{"key":"2025032619371449300_R14","first-page":"1057","article-title":"Control of regulatory T cell development by the transcription factor Foxp3.","volume-title":"Science","year":"2003"},{"key":"2025032619371449300_R15","first-page":"889","article-title":"Forkhead-box transcription factors and their role in the immune system.","volume-title":"Nat. Rev.","year":"2004"},{"key":"2025032619371449300_R16","first-page":"627","article-title":"Emerging challenges in regulatory T cell function and biology.","volume-title":"Science","year":"2007"},{"key":"2025032619371449300_R17","first-page":"816","article-title":"Regulatory T cells in the control of immune pathology.","volume-title":"Nat. Immunol.","year":"2001"},{"key":"2025032619371449300_R18","first-page":"389","article-title":"CD4+CD25+ suppressor T cells: more questions than answers.","volume-title":"Nat. Rev.","year":"2002"},{"key":"2025032619371449300_R19","first-page":"1322","article-title":"Prevalence of newly generated naive regulatory T cells (Treg) is critical for Treg suppressive function and determines Treg dysfunction in multiple sclerosis.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032619371449300_R20","first-page":"209","article-title":"FOXP3: of mice and men.","volume-title":"Annu. Rev. Immunol.","year":"2006"},{"key":"2025032619371449300_R21","first-page":"345","article-title":"Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.","volume-title":"Nat. Immunol.","year":"2005"},{"key":"2025032619371449300_R22","first-page":"15","article-title":"Regulatory T cells.","volume-title":"J. Invest. Dermatol.","year":"2006"},{"key":"2025032619371449300_R23","first-page":"613","article-title":"The GITR-GITRL interaction: co-stimulation or contrasuppression of regulatory activity?.","volume-title":"Nat. Rev.","year":"2006"},{"key":"2025032619371449300_R24","first-page":"68","article-title":"Disruption of a new forkhead\/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.","volume-title":"Nat. Genet.","year":"2001"},{"key":"2025032619371449300_R25","first-page":"18","article-title":"X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.","volume-title":"Nat. Genet.","year":"2001"},{"key":"2025032619371449300_R26","first-page":"971","article-title":"Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis.","volume-title":"J. Exp. Med.","year":"2004"},{"key":"2025032619371449300_R27","first-page":"45","article-title":"Decreased FOXP3 levels in multiple sclerosis patients.","volume-title":"J. Neurosci. Res.","year":"2005"},{"key":"2025032619371449300_R28","first-page":"79","article-title":"Compromised CD4+CD25high regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level.","volume-title":"Immunology","year":"2008"},{"key":"2025032619371449300_R29","first-page":"44527","article-title":"Ligation of CD40 stimulates the induction of nitric-oxide synthase in microglial cells.","volume-title":"J. Biol. Chem.","year":"2001"},{"key":"2025032619371449300_R30","first-page":"934","article-title":"Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis independent of peroxisome proliferator-activated receptor-\u03b1.","volume-title":"Mol. Pharmacol.","year":"2007"},{"key":"2025032619371449300_R31","first-page":"275","article-title":"Sodium benzoate, a food additive and a metabolite of cinnamon, modifies T cells at multiple steps and inhibits adoptive transfer of experimental allergic encephalomyelitis.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032619371449300_R32","first-page":"14971","article-title":"Up-regulation of microglial CD11b expression by nitric oxide.","volume-title":"J. Biol. Chem.","year":"2006"},{"key":"2025032619371449300_R33","first-page":"4142","article-title":"Involvement of phosphatidylinositol 3-kinase-mediated up-regulation of I\u03baB\u03b1 in anti-inflammatory effect of gemfibrozil in microglia.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032619371449300_R34","first-page":"39327","article-title":"Myelin basic protein-primed T cells induce nitric oxide synthase in microglial cells. Implications for multiple sclerosis.","volume-title":"J. Biol. Chem.","year":"2002"},{"key":"2025032619371449300_R35","first-page":"32222","article-title":"Myelin basic protein-primed T cells induce neurotrophins in glial cells via \u03b15\u03b23 integrin.","volume-title":"J. Biol. Chem.","year":"2007"},{"key":"2025032619371449300_R36","first-page":"22424","article-title":"Role of very-late antigen-4 (VLA-4) in myelin basic protein-primed T cell contact-induced expression of proinflammatory cytokines in microglial cells.","volume-title":"J. Biol. Chem.","year":"2003"},{"key":"2025032619371449300_R37","first-page":"4930","article-title":"Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide.","volume-title":"J. Neurosci.","year":"2006"},{"key":"2025032619371449300_R38","first-page":"18754","article-title":"Selective inhibition of NF-\u03baB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson\u2019s disease.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2007"},{"key":"2025032619371449300_R39","first-page":"931","article-title":"Foxp3 occupancy and regulation of key target genes during T-cell stimulation.","volume-title":"Nature","year":"2007"},{"key":"2025032619371449300_R40","first-page":"627","article-title":"Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells.","volume-title":"Cell Res.","year":"2007"},{"key":"2025032619371449300_R41","first-page":"743","article-title":"Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue.","volume-title":"Gut","year":"2009"},{"key":"2025032619371449300_R42","first-page":"2007","article-title":"Characterization of mouse interleukin-12 p40 homodimer binding to the interleukin-12 receptor subunits.","volume-title":"Eur. J. Immunol.","year":"1999"},{"key":"2025032619371449300_R43","first-page":"16186","article-title":"Nitric oxide preferentially induces type 1 T cell differentiation by selectively up-regulating IL-12 receptor \u03b22 expression via cGMP.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2002"},{"key":"2025032619371449300_R44","first-page":"547","article-title":"Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages.","volume-title":"Science","year":"1993"},{"key":"2025032619371449300_R45","first-page":"500","article-title":"The IL-12 p40 homodimer as a specific antagonist of the IL-12 heterodimer.","volume-title":"Immunol. Today","year":"1995"},{"key":"2025032619371449300_R46","first-page":"519","article-title":"Induction of tumor necrosis factor-\u03b1 (TNF-\u03b1) by interleukin-12 p40 monomer and homodimer in microglia and macrophages.","volume-title":"J. Neurochem.","year":"2003"},{"key":"2025032619371449300_R47","first-page":"3097","article-title":"Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo.","volume-title":"Blood","year":"2005"},{"key":"2025032619371449300_R48","first-page":"671","article-title":"Transforming growth factor \u03b2 induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis.","volume-title":"Gut","year":"2006"},{"key":"2025032619371449300_R49","first-page":"2041","article-title":"Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4+ CD25 T cells.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032619371449300_R50","first-page":"227","article-title":"Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer.","volume-title":"J. Leukocyte Biol.","year":"2006"},{"key":"2025032619371449300_R51","first-page":"45","article-title":"Soluble interleukin-6 receptors in inflammatory bowel disease: relation to circulating interleukin-6.","volume-title":"Gut","year":"1995"},{"key":"2025032619371449300_R52","first-page":"79","article-title":"Compromised CD4+CD25high regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level.","volume-title":"Immunology","year":"2008"},{"key":"2025032619371449300_R53","first-page":"116","article-title":"Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity.","volume-title":"J. Immunol.","year":"1995"},{"key":"2025032619371449300_R54","first-page":"200","article-title":"Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist.","volume-title":"Eur. J. Immunol.","year":"1995"},{"key":"2025032619371449300_R55","first-page":"6866","article-title":"IL-12 p40 homodimer-dependent macrophage chemotaxis and respiratory viral inflammation are mediated through IL-12 receptor \u03b21.","volume-title":"J. Immunol.","year":"2003"},{"key":"2025032619371449300_R56","first-page":"778","article-title":"Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains.","volume-title":"Ann. Neurol.","year":"1994"},{"key":"2025032619371449300_R57","first-page":"1456","article-title":"Sequence identity in the nick regions of IncP plasmid transfer origins and T-DNA borders of Agrobacterium Ti plasmids.","volume-title":"Proc. Natl. Acad. Sci. 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