{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:04:29Z","timestamp":1792523069749,"version":"4.5.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T00:00:00Z","timestamp":1396310400000},"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":[[2014,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Nerve growth factor (NGF) levels are highly increased in inflamed tissues, but their role is unclear. We show that NGF is part of a regulatory loop in monocytes: inflammatory stimuli, while activating a proinflammatory response through TLRs, upregulate the expression of the NGF receptor TrkA. In turn, NGF, by binding to TrkA, interferes with TLR responses. In TLR-activated monocytes, NGF reduces inflammatory cytokine production (IL-1\u03b2, TNF-\u03b1, IL-6, and IL-8) while inducing the release of anti-inflammatory mediators (IL-10 and IL-1 receptor antagonist). NGF binding to TrkA affects TLR signaling, favoring pathways that mediate inhibition of inflammatory responses: it increases Akt phosphorylation, inhibits glycogen synthase kinase 3 activity, reduces I\u03baB phosphorylation and p65 NF-\u03baB translocation, and increases nuclear p50 NF-\u03baB binding activity. Use of TrkA inhibitors in TLR-activated monocytes abolishes the effects of NGF on the activation of anti-inflammatory signaling pathways, thus increasing NF-\u03baB pathway activation and inflammatory cytokine production while reducing IL-10 production. PBMC and mononuclear cells obtained from the synovial fluid of patients with juvenile idiopathic arthritis show marked downregulation of TrkA expression. In ex vivo experiments, the addition of NGF to LPS-activated juvenile idiopathic arthritis to both mononuclear cells from synovial fluid and PBMC fails to reduce the production of IL-6 that, in contrast, is observed in healthy donors. This suggests that defective TrkA expression may facilitate proinflammatory mechanisms, contributing to chronic tissue inflammation and damage. In conclusion, this study identifies a novel regulatory mechanism of inflammatory responses through NGF and its receptor TrkA, for which abnormality may have pathogenic implications for chronic inflammatory diseases.<\/jats:p>","DOI":"10.4049\/jimmunol.1300825","type":"journal-article","created":{"date-parts":[[2014,3,1]],"date-time":"2014-03-01T02:39:12Z","timestamp":1393641552000},"page":"3345-3354","source":"Crossref","is-referenced-by-count":113,"title":["Nerve Growth Factor Downregulates Inflammatory Response in Human Monocytes through TrkA"],"prefix":"10.1093","volume":"192","author":[{"given":"Giusi","family":"Prencipe","sequence":"first","affiliation":[{"name":"Research Laboratories, Unit of Rheumatology, Bambino Ges\u00f9 Children\u2019s Hospital , 00165 Rome,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetana","family":"Minnone","sequence":"additional","affiliation":[{"name":"Research Laboratories, Unit of Rheumatology, Bambino Ges\u00f9 Children\u2019s Hospital , 00165 Rome,","place":["Italy"]},{"name":"Department of Medicine, \u201cTor Vergata\u201d University , Rome 00173,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Strippoli","sequence":"additional","affiliation":[{"name":"Research Laboratories, Unit of Rheumatology, Bambino Ges\u00f9 Children\u2019s Hospital , 00165 Rome,","place":["Italy"]},{"name":"Department of Cellular Biotechnologies and Haematology, University of Rome La Sapienza , Rome 00185,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loredana","family":"De Pasquale","sequence":"additional","affiliation":[{"name":"Research Laboratories, Unit of Rheumatology, Bambino Ges\u00f9 Children\u2019s Hospital , 00165 Rome,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Petrini","sequence":"additional","affiliation":[{"name":"Research Laboratories, Confocal Microscopy Core Facility, Bambino Ges\u00f9 Children\u2019s Hospital , 00165 Rome,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Caiello","sequence":"additional","affiliation":[{"name":"Research Laboratories, Unit of Rheumatology, Bambino Ges\u00f9 Children\u2019s Hospital , 00165 Rome,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Manni","sequence":"additional","affiliation":[{"name":"Institute of Translational Pharmacology, National Research Council , 00133 Rome,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"De Benedetti","sequence":"additional","affiliation":[{"name":"Research Laboratories, Unit of Rheumatology, Bambino Ges\u00f9 Children\u2019s Hospital , 00165 Rome,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Bracci-Laudiero","sequence":"additional","affiliation":[{"name":"Research Laboratories, Unit of Rheumatology, Bambino Ges\u00f9 Children\u2019s Hospital , 00165 Rome,","place":["Italy"]},{"name":"Institute of Translational Pharmacology, National Research Council , 00133 Rome,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,4,1]]},"reference":[{"key":"2025032404202583100_r1","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1126\/science.3306916","article-title":"The nerve growth factor 35 years later","volume":"237","author":"Levi-Montalcini","year":"1987","journal-title":"Science"},{"key":"2025032404202583100_r2","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1146\/annurev.neuro.24.1.1217","article-title":"Nerve growth factor signaling, neuroprotection, and neural repair","volume":"24","author":"Sofroniew","year":"2001","journal-title":"Annu. Rev. Neurosci."},{"key":"2025032404202583100_r3","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.semarthrit.2009.03.002","article-title":"Nerve growth factor in rheumatic diseases","volume":"40","author":"Seidel","year":"2010","journal-title":"Semin. Arthritis Rheum."},{"key":"2025032404202583100_r4"},{"key":"2025032404202583100_r5","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1084\/jem.191.10.1799","article-title":"Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system","volume":"191","author":"Villoslada","year":"2000","journal-title":"J. Exp. Med."},{"key":"2025032404202583100_r6","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.cyto.2007.04.005","article-title":"Up-regulation of nerve growth factor and interleukin-10 in inflamed and non-inflamed intestinal segments in rats with experimental colitis","volume":"37","author":"Barada","year":"2007","journal-title":"Cytokine"},{"key":"2025032404202583100_r7","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1053\/gast.2000.9307","article-title":"Protective role of neurotrophins in experimental inflammation of the rat gut","volume":"119","author":"Reinshagen","year":"2000","journal-title":"Gastroenterology"},{"key":"2025032404202583100_r8","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1046\/j.0022-202x.2001.01679.x","article-title":"Nerve growth factor, neuropeptides, and mast cells in ultraviolet-B-induced systemic suppression of contact hypersensitivity responses in mice","volume":"118","author":"Townley","year":"2002","journal-title":"J. Invest. Dermatol."},{"key":"2025032404202583100_r9","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1098\/rstb.2006.1894","article-title":"Neurotrophin-regulated signalling pathways","volume":"361","author":"Reichardt","year":"2006","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"2025032404202583100_r10","doi-asserted-by":"crossref","first-page":"4965","DOI":"10.4049\/jimmunol.154.10.4965","article-title":"Nerve growth factor induces activation of MAP-kinase and p90rsk in human B lymphocytes","volume":"154","author":"Franklin","year":"1995","journal-title":"J. Immunol."},{"key":"2025032404202583100_r11","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1002\/eji.1830260903","article-title":"Nerve growth factor signal transduction in human B lymphocytes is mediated by gp140trk","volume":"26","author":"Melamed","year":"1996","journal-title":"Eur. J. Immunol."},{"key":"2025032404202583100_r12","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1002\/1521-4141(200201)32:1<136::AID-IMMU136>3.0.CO;2-T","article-title":"NGF rescues human B lymphocytes from anti-IgM induced apoptosis by activation of PKCzeta","volume":"32","author":"Kronfeld","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"2025032404202583100_r13","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.cell.2006.02.015","article-title":"Pathogen recognition and innate immunity","volume":"124","author":"Akira","year":"2006","journal-title":"Cell"},{"key":"2025032404202583100_r14","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.molmed.2007.09.002","article-title":"Signaling to NF-kappaB by Toll-like receptors","volume":"13","author":"Kawai","year":"2007","journal-title":"Trends Mol. Med."},{"key":"2025032404202583100_r15","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.coi.2005.11.012","article-title":"How Toll-like receptors signal: what we know and what we don\u2019t know","volume":"18","author":"O\u2019Neill","year":"2006","journal-title":"Curr. Opin. Immunol."},{"key":"2025032404202583100_r16","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1038\/ni1274","article-title":"Limiting inflammatory responses during activation of innate immunity","volume":"6","author":"Han","year":"2005","journal-title":"Nat. Immunol."},{"key":"2025032404202583100_r17","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1126\/science.1183021","article-title":"Regulation of adaptive immunity by the innate immune system","volume":"327","author":"Iwasaki","year":"2010","journal-title":"Science"},{"key":"2025032404202583100_r18","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.biocel.2009.10.010","article-title":"TLRs and chronic inflammation","volume":"42","author":"Ospelt","year":"2010","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2025032404202583100_r19","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1093\/rheumatology\/ker257","article-title":"Intrinsic danger: activation of Toll-like receptors in rheumatoid arthritis","volume":"51","author":"Goh","year":"2012","journal-title":"Rheumatology (Oxford)"},{"key":"2025032404202583100_r20","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0165-5728(00)00441-0","article-title":"Human monocyte\/macrophages activate by exposure to LPS overexpress NGF and NGF receptors","volume":"113","author":"Caroleo","year":"2001","journal-title":"J. Neuroimmunol."},{"key":"2025032404202583100_r21","doi-asserted-by":"crossref","first-page":"5423","DOI":"10.1073\/pnas.90.12.5423","article-title":"Expression of functional trk protooncogene in human monocytes","volume":"90","author":"Ehrhard","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032404202583100_r22","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1073\/pnas.64.2.787","article-title":"The nerve growth factor: purification as a 30,000-molecular-weight protein","volume":"64","author":"Bocchini","year":"1969","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032404202583100_r23","doi-asserted-by":"crossref","first-page":"3507","DOI":"10.1182\/blood-2004-10-4055","article-title":"Endogenous NGF regulates CGRP expression in human monocytes, and affects HLA-DR and CD86 expression and IL-10 production","volume":"106","author":"Bracci-Laudiero","year":"2005","journal-title":"Blood"},{"key":"2025032404202583100_r24","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"2025032404202583100_r25","doi-asserted-by":"crossref","first-page":"E21","DOI":"10.1093\/nar\/29.4.e21","article-title":"Development of a sensitive multi-well colorimetric assay for active NFkappaB","volume":"29","author":"Renard","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"2025032404202583100_r26","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/nrrheum.2009.209","article-title":"Oligoarticular and polyarticular JIA: epidemiology and pathogenesis","volume":"5","author":"Macaubas","year":"2009","journal-title":"Nat. Rev. Rheumatol."},{"key":"2025032404202583100_r27","doi-asserted-by":"crossref","first-page":"446","DOI":"10.4049\/jimmunol.178.1.446","article-title":"Opposite regulation of IL-1beta and secreted IL-1 receptor antagonist production by phosphatidylinositide-3 kinases in human monocytes activated by lipopolysaccharides or contact with T cells","volume":"178","author":"Molnarfi","year":"2007","journal-title":"J. Immunol."},{"key":"2025032404202583100_r28","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/nri1630","article-title":"Negative regulation of toll-like receptor-mediated immune responses","volume":"5","author":"Liew","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"2025032404202583100_r29","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/S1471-4906(03)00139-X","article-title":"PI3K and negative regulation of TLR signaling","volume":"24","author":"Fukao","year":"2003","journal-title":"Trends Immunol."},{"key":"2025032404202583100_r30","doi-asserted-by":"crossref","first-page":"32124","DOI":"10.1074\/jbc.M203298200","article-title":"The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells","volume":"277","author":"Guha","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2025032404202583100_r31","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.imlet.2004.12.007","article-title":"LY294002 inhibits LPS-induced NO production through a inhibition of NF-kappaB activation: independent mechanism of phosphatidylinositol 3-kinase","volume":"99","author":"Kim","year":"2005","journal-title":"Immunol. Lett."},{"key":"2025032404202583100_r32","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.1074\/jbc.M311512200","article-title":"Glycogen synthase kinase-3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35. Implications for Alzheimer\u2019s disease","volume":"279","author":"Hern\u00e1ndez","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2025032404202583100_r33","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/nm0895-774","article-title":"The biological effects of endogenous nerve growth factor on adult sensory neurons revealed by a trkA-IgG fusion molecule","volume":"1","author":"McMahon","year":"1995","journal-title":"Nat. Med."},{"key":"2025032404202583100_r34","doi-asserted-by":"crossref","first-page":"2985","DOI":"10.1073\/pnas.0611253104","article-title":"The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain","volume":"104","author":"Ugolini","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032404202583100_r35","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1189\/jlb.68.1.104","article-title":"Ligand activation of nerve growth factor receptor TrkA protects monocytes from apoptosis","volume":"68","author":"la Sala","year":"2000","journal-title":"J. Leukoc. Biol."},{"key":"2025032404202583100_r36","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.immuni.2006.02.014","article-title":"IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB\/AP-1 proteins","volume":"24","author":"Hu","year":"2006","journal-title":"Immunity"},{"key":"2025032404202583100_r37","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.it.2009.09.007","article-title":"Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3)","volume":"31","author":"Beurel","year":"2010","journal-title":"Trends Immunol."},{"key":"2025032404202583100_r38","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1111\/j.1365-2567.2010.03402.x","article-title":"Interleukin-10-induced gene expression and suppressive function are selectively modulated by the PI3K-Akt-GSK3 pathway","volume":"132","author":"Antoniv","year":"2011","journal-title":"Immunology"},{"key":"2025032404202583100_r39","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1124\/mol.105.021162","article-title":"Opposite effects of wortmannin and 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride on toll-like receptor-mediated nitric oxide production: negative regulation of nuclear factor-kappaB by phosphoinositide 3-kinase","volume":"69","author":"Hazeki","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"2025032404202583100_r40","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/nri2423","article-title":"New regulators of NF-kappaB in inflammation","volume":"8","author":"Ghosh","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"2025032404202583100_r41","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1172\/JCI3877","article-title":"Regulation of an essential innate immune response by the p50 subunit of NF-kappaB","volume":"102","author":"Bohuslav","year":"1998","journal-title":"J. Clin. Invest."},{"key":"2025032404202583100_r42","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1002\/1521-4141(200102)31:2<625::AID-IMMU625>3.0.CO;2-H","article-title":"Role of nerve growth factor in experimental autoimmune encephalomyelitis","volume":"31","author":"Arredondo","year":"2001","journal-title":"Eur. J. Immunol."},{"key":"2025032404202583100_r43","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/1521-4141(200101)31:1<11::AID-IMMU11>3.0.CO;2-G","article-title":"Anti-inflammatory activity of nerve growth factor in experimental autoimmune encephalomyelitis: inhibition of monocyte transendothelial migration","volume":"31","author":"Fl\u00fcgel","year":"2001","journal-title":"Eur. J. Immunol."},{"key":"2025032404202583100_r44","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/S0165-5728(99)00272-6","article-title":"Nerve growth factor antibody exacerbates neuropathological signs of experimental allergic encephalomyelitis in adult lewis rats","volume":"104","author":"Micera","year":"2000","journal-title":"J. Neuroimmunol."},{"key":"2025032404202583100_r45","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1136\/ard.55.10.745","article-title":"Increased circulating nerve growth factor is directly correlated with disease activity in juvenile chronic arthritis","volume":"55","author":"Falcini","year":"1996","journal-title":"Ann. Rheum. Dis."},{"key":"2025032404202583100_r46","doi-asserted-by":"crossref","first-page":"R82","DOI":"10.1186\/ar2716","article-title":"Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis","volume":"11","author":"Barthel","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"2025032404202583100_r47","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/art.1780350315","article-title":"Nerve growth factor in the synovial fluid of patients with chronic arthritis","volume":"35","author":"Aloe","year":"1992","journal-title":"Arthritis Rheum."},{"key":"2025032404202583100_r48","doi-asserted-by":"crossref","first-page":"349","DOI":"10.2165\/0063030-200822060-00002","article-title":"Targeting nerve growth factor in pain: what is the therapeutic potential?","volume":"22","author":"Watson","year":"2008","journal-title":"BioDrugs"},{"key":"2025032404202583100_r49","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1517\/13543770902721261","article-title":"Trk kinase inhibitors as new treatments for cancer and pain","volume":"19","author":"Wang","year":"2009","journal-title":"Expert Opin. Ther. Pat."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/192\/7\/3345\/61758351\/1300825.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/192\/7\/3345\/61758351\/1300825.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T07:31:37Z","timestamp":1742801497000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/192\/7\/3345\/8001383"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,1]]},"references-count":49,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2014,4,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1300825","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,4]]},"published":{"date-parts":[[2014,4,1]]}}}