{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:55:09Z","timestamp":1787316909360,"version":"build-2736575974"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Stuart Bainum and The Foundation for the Greater Good"},{"name":"Mary Nell and George Berry"},{"name":"William Damora"},{"name":"Gloria and Edward Felsenthal"},{"name":"Ruth Frey"},{"name":"Shirley Griffin"},{"name":"Ruth and George Harms"},{"name":"Yancey and David Hillegas"},{"name":"Diantha Johnson"},{"name":"Bassem Kudsi"},{"name":"Judy Lewent and Mark Shapiro"},{"name":"Terrence O\u2019Donnell"},{"name":"Jay Ripley"},{"name":"Israel Vainboim"},{"name":"The Health Network Foundation"},{"name":"the Met Life Foundation"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>The 104 aa protein Serum Amyloid A (SAA) is a prominent member of the acute phase response (APR) a remarkably conserved and stereotyped set of serum protein changes associated with inflammation and other stimuli. N-terminal fragments of SAA can form fibrils that accumulate in organs (where they are called \u201camyloidosis\u201d). Recent reports have shown SAA involvement in inflammation, particularly with macrophages, consistent with its role as a \u201cbiomarker.\u201d In contrast to this perception of passivity, we report that exposure to both N-terminal decapeptides and intact SAA monomers can induce multiple transcripts in both enteroids and HEK293 cells. The spectrum of transcripts prominently includes proteins related to inflammation and NF-\u03baB control, specifically NFKB1A, TNFA1P3 and IER3. SAA thus can act directly through specific transcription to alter cellular physiology in cells outside the monocyte\/macrophage lineage with direct effects on inflammation, likely helping explain its remarkable evolutionary conservation as part of primordial defense.<\/jats:p>","DOI":"10.1371\/journal.pone.0341858","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T18:37:53Z","timestamp":1771526273000},"page":"e0341858","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Serum Amyloid A (SAA) induces transcription affecting inflammation"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9307-6263","authenticated-orcid":true,"given":"George H.","family":"Sack","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Yun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Conover","family":"Talbot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmeet","family":"Sethi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"issue":"1","key":"pone.0341858.ref001","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s10020-018-0047-0","article-title":"Serum amyloid A - a review","volume":"24","author":"GH Sack","year":"2018","journal-title":"Mol Med"},{"key":"pone.0341858.ref002","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S0065-2776(08)60379-X","article-title":"Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein","volume":"34","author":"MB Pepys","year":"1983","journal-title":"Adv Immunol"},{"issue":"14","key":"pone.0341858.ref003","doi-asserted-by":"crossref","first-page":"5189","DOI":"10.1073\/pnas.1322357111","article-title":"Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis","volume":"111","author":"J Lu","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"pone.0341858.ref004","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1002\/1873-3468.12116","article-title":"Structure of serum amyloid A suggests a mechanism for selective lipoprotein binding and functions: SAA as a hub in macromolecular interaction networks","volume":"590","author":"NM Frame","year":"2016","journal-title":"FEBS Lett"},{"issue":"8","key":"pone.0341858.ref005","doi-asserted-by":"crossref","first-page":"4718","DOI":"10.1073\/pnas.78.8.4718","article-title":"Induction of hepatic synthesis of serum amyloid A protein and actin","volume":"78","author":"JF Morrow","year":"1981","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0341858.ref006","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/0378-1119(83)90143-9","article-title":"Molecular cloning of human genes for serum amyloid A","volume":"21","author":"GH Sack","year":"1983","journal-title":"Gene"},{"issue":"22","key":"pone.0341858.ref007","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1056\/NEJM198411293112205","article-title":"Interleukin-1 and the pathogenesis of the acute-phase response","volume":"311","author":"CA Dinarello","year":"1984","journal-title":"N Engl J Med"},{"issue":"5","key":"pone.0341858.ref008","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/1043-4666(91)90041-B","article-title":"Constitutive and NF-kappa B-like proteins in the regulation of the serum amyloid A gene by interleukin 1","volume":"3","author":"MR Edbrooke","year":"1991","journal-title":"Cytokine"},{"issue":"34","key":"pone.0341858.ref009","doi-asserted-by":"crossref","first-page":"25624","DOI":"10.1016\/S0021-9258(19)74435-4","article-title":"The role of NF-kappa B and NF-IL6 transactivating factors in the synergistic activation of human serum amyloid A gene expression by interleukin-1 and interleukin-6","volume":"268","author":"JC Betts","year":"1993","journal-title":"J Biol Chem"},{"issue":"4","key":"pone.0341858.ref010","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1158\/2159-8290.CD-21-0692","article-title":"Subversion of Serotonin Receptor Signaling in Osteoblasts by Kynurenine Drives Acute Myeloid Leukemia","volume":"12","author":"M Gal\u00e1n-D\u00edez","year":"2022","journal-title":"Cancer Discov"},{"issue":"3","key":"pone.0341858.ref011","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.cell.2009.09.033","article-title":"Induction of intestinal Th17 cells by segmented filamentous bacteria","volume":"139","author":"II Ivanov","year":"2009","journal-title":"Cell"},{"issue":"19","key":"pone.0341858.ref012","doi-asserted-by":"crossref","first-page":"18562","DOI":"10.1074\/jbc.M500490200","article-title":"Serum amyloid A protein binds to outer membrane protein A of gram-negative bacteria","volume":"280","author":"R Hari-Dass","year":"2005","journal-title":"J Biol Chem"},{"issue":"5","key":"pone.0341858.ref013","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1182\/blood-2005-11-011932","article-title":"Serum amyloid A is an innate immune opsonin for Gram-negative bacteria","volume":"108","author":"C Shah","year":"2006","journal-title":"Blood"},{"issue":"5","key":"pone.0341858.ref014","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.3390\/cells10051264","article-title":"Mycobacterium tuberculosis Binds Human Serum Amyloid A, and the Interaction Modulates the Colonization of Human Macrophages and the Transcriptional Response of the Pathogen","volume":"10","author":"M Kawka","year":"2021","journal-title":"Cells"},{"key":"pone.0341858.ref015","doi-asserted-by":"crossref","first-page":"1238132","DOI":"10.3389\/fimmu.2023.1238132","article-title":"The functional response of human monocyte-derived macrophages to serum amyloid A and Mycobacterium tuberculosis infection","volume":"14","author":"M Kawka","year":"2023","journal-title":"Front Immunol"},{"key":"pone.0341858.ref016","doi-asserted-by":"crossref","first-page":"691155","DOI":"10.3389\/fimmu.2021.691155","article-title":"Serum Amyloid A1 Induces Classically Activated Macrophages: A Role for Enhanced Fibril Formation","volume":"12","author":"A-K Gaiser","year":"2021","journal-title":"Front Immunol"},{"key":"pone.0341858.ref017","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0165-2427(01)00380-4","article-title":"Elevated extrahepatic expression and secretion of mammary-associated serum amyloid A 3 (M-SAA3) into colostrum","volume":"83","author":"TL McDonald","year":"2001","journal-title":"Vet Immunol Immunopathol"},{"issue":"2","key":"pone.0341858.ref018","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S0006-291X(02)02901-7","article-title":"Human serum amyloid A3 peptide enhances intestinal MUC3 expression and inhibits EPEC adherence","volume":"300","author":"MA Larson","year":"2003","journal-title":"Biochem Biophys Res Commun"},{"issue":"18","key":"pone.0341858.ref019","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1101\/gad.1228704","article-title":"Signaling to NF-kappaB","volume":"18","author":"MS Hayden","year":"2004","journal-title":"Genes Dev"},{"issue":"11","key":"pone.0341858.ref020","doi-asserted-by":"crossref","first-page":"3931","DOI":"10.1111\/jog.14947","article-title":"Study on the effect and mechanism of NFKBIA on cervical cancer progress in vitro and in vivo","volume":"47","author":"M Chen","year":"2021","journal-title":"J Obstet Gynaecol Res"},{"issue":"5596","key":"pone.0341858.ref021","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1126\/science.1071914","article-title":"The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation","volume":"298","author":"A Hoffmann","year":"2002","journal-title":"Science"},{"issue":"7000","key":"pone.0341858.ref022","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/nature02794","article-title":"De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling","volume":"430","author":"IE Wertz","year":"2004","journal-title":"Nature"},{"issue":"8","key":"pone.0341858.ref023","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.it.2009.05.007","article-title":"The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology","volume":"30","author":"L Vereecke","year":"2009","journal-title":"Trends Immunol"},{"issue":"8","key":"pone.0341858.ref024","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/s41584-022-00778-4","article-title":"Disorders of ubiquitylation: unchained inflammation","volume":"18","author":"DB Beck","year":"2022","journal-title":"Nat Rev Rheumatol"},{"issue":"3","key":"pone.0341858.ref025","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/wsbm.1331","article-title":"Signaling via the NF\u03baB system","volume":"8","author":"S Mitchell","year":"2016","journal-title":"Wiley Interdiscip Rev Syst Biol Med"},{"key":"pone.0341858.ref026","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.ejcb.2010.10.002","article-title":"Role of the immediate early response 3 (IER3) gene in cellular stress response, inflammation and tumorigenesis","volume":"90","author":"A Arlt","year":"2011","journal-title":"Eur J Cell Biol"},{"issue":"5","key":"pone.0341858.ref027","first-page":"1397","article-title":"Molecular cloning and characterization of human ERM, a new member of the Ets family closely related to mouse PEA3 and ER81 transcription factors","volume":"9","author":"D Mont\u00e9","year":"1994","journal-title":"Oncogene"},{"issue":"1","key":"pone.0341858.ref028","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1186\/s13048-021-00899-6","article-title":"Biological and prognostic value of ETV5 in high-grade serous ovarian cancer","volume":"14","author":"L Zhang","year":"2021","journal-title":"J Ovarian Res"},{"issue":"10","key":"pone.0341858.ref029","doi-asserted-by":"crossref","first-page":"2546","DOI":"10.1046\/j.1432-1033.2002.02921.x","article-title":"Human sprouty 4, a new ras antagonist on 5q31, interacts with the dual specificity kinase TESK1","volume":"269","author":"OC Leeksma","year":"2002","journal-title":"Eur J Biochem"},{"issue":"1","key":"pone.0341858.ref030","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.tcb.2005.11.004","article-title":"Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling","volume":"16","author":"JM Mason","year":"2006","journal-title":"Trends Cell Biol"},{"issue":"7","key":"pone.0341858.ref031","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1515\/bc.2010.082","article-title":"Sprouty4 levels are increased under hypoxic conditions by enhanced mRNA stability and transcription","volume":"391","author":"B Haigl","year":"2010","journal-title":"Biol Chem"},{"key":"pone.0341858.ref032","doi-asserted-by":"crossref","first-page":"1376873","DOI":"10.3389\/fonc.2024.1376873","article-title":"Role of SPRY4 in health and disease","volume":"14","author":"H Pan","year":"2024","journal-title":"Front Oncol"},{"issue":"1","key":"pone.0341858.ref033","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41413-024-00364-2","article-title":"A monoallelic variant in CCN2 causes an autosomal dominant spondyloepimetaphyseal dysplasia with low bone mass","volume":"12","author":"S Li","year":"2024","journal-title":"Bone Res"},{"issue":"1","key":"pone.0341858.ref034","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1186\/s12931-023-02512-4","article-title":"CTGF promotes the repair and regeneration of alveoli after acute lung injury by promoting the proliferation of subpopulation of AEC2s","volume":"24","author":"J Sun","year":"2023","journal-title":"Respir Res"},{"key":"pone.0341858.ref035","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/0378-1119(94)90676-9","article-title":"Structural organisation and chromosomal mapping of the human Id-3 gene","volume":"151","author":"RW Deed","year":"1994","journal-title":"Gene"},{"issue":"32","key":"pone.0341858.ref036","doi-asserted-by":"crossref","first-page":"19785","DOI":"10.1074\/jbc.272.32.19785","article-title":"Differential interactions of Id proteins with basic-helix-loop-helix transcription factors","volume":"272","author":"K Langlands","year":"1997","journal-title":"J Biol Chem"},{"issue":"6","key":"pone.0341858.ref037","doi-asserted-by":"crossref","first-page":"4313","DOI":"10.1074\/jbc.M412614200","article-title":"Nucleo-cytoplasmic shuttling of Id2, a negative regulator of basic helix-loop-helix transcription factors","volume":"280","author":"H Kurooka","year":"2005","journal-title":"J Biol Chem"},{"issue":"20","key":"pone.0341858.ref038","doi-asserted-by":"crossref","first-page":"5417","DOI":"10.1093\/emboj\/cdf549","article-title":"SHARP is a novel component of the Notch\/RBP-Jkappa signalling pathway","volume":"21","author":"F Oswald","year":"2002","journal-title":"EMBO J"},{"issue":"19","key":"pone.0341858.ref039","doi-asserted-by":"crossref","first-page":"4857","DOI":"10.1016\/j.cell.2021.08.013","article-title":"The expanding amyloid family: Structure, stability, function, and pathogenesis","volume":"184","author":"MR Sawaya","year":"2021","journal-title":"Cell"},{"issue":"2","key":"pone.0341858.ref040","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/0378-1119(89)90528-3","article-title":"The human serum amyloid A (SAA)-encoding gene GSAA1: nucleotide sequence and possible autocrine-collagenase-inducer function","volume":"84","author":"GH Sack","year":"1989","journal-title":"Gene"},{"issue":"3","key":"pone.0341858.ref041","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.4049\/jimmunol.1700470","article-title":"Suppression of Lipopolysaccharide-Induced Inflammatory Response by Fragments from Serum Amyloid A","volume":"199","author":"H Zhou","year":"2017","journal-title":"J Immunol"},{"issue":"7368","key":"pone.0341858.ref042","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature10491","article-title":"An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor","volume":"478","author":"CA Opitz","year":"2011","journal-title":"Nature"},{"key":"pone.0341858.ref043","doi-asserted-by":"crossref","first-page":"1544085","DOI":"10.3389\/fimmu.2025.1544085","article-title":"Balancing inflammation: the specific roles of serum amyloid A proteins in sterile and infectious diseases","volume":"16","author":"T Mohanty","year":"2025","journal-title":"Front Immunol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0341858","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T18:37:58Z","timestamp":1771526278000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0341858"}},"subtitle":[],"editor":[{"given":"Henning","family":"Ulrich","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,2,19]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2,19]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0341858","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,19]]}}}