{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T22:40:00Z","timestamp":1782859200201,"version":"3.54.5"},"reference-count":39,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T00:00:00Z","timestamp":1702598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>T cell depletion and functional impairment are characteristics of sepsis. CD137 is a costimulatory receptor on activated T cells, while soluble CD137 (sCD137) inhibits CD137 signaling. This study found elevated sCD137 levels in the plasma of patients with systemic inflammatory response syndrome (SIRS), sepsis, or septic shock compared to healthy controls. The sCD137 levels negatively correlated with the C-reactive protein and positively with procalcitonin and interleukin-6. There was no difference in sCD137 levels based on ventilation, dialysis, or vasopressor treatment. Patients with SARS-CoV-2, Gram-positive, or Gram-negative bacterial infections had similar sCD137 levels as noninfected individuals. Notably, higher plasma sCD137 levels were observed in non-survivors compared to survivors in both the SIRS\/sepsis group and the SARS-CoV-2 subgroup. In conclusion, plasma sCD137 levels are associated with severe illness and survival in critically ill patients.<\/jats:p>","DOI":"10.3390\/ijms242417518","type":"journal-article","created":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T08:12:57Z","timestamp":1702627977000},"page":"17518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Soluble CD137: A Potential Prognostic Biomarker in Critically Ill Patients"],"prefix":"10.3390","volume":"24","author":[{"given":"Ulrich","family":"R\u00e4th","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Mester","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3558-3424","authenticated-orcid":false,"given":"Herbert","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Department of Physiology, and Immunology Programme, Yong Loo Lin School of Medicine, National University of Singapore, MD9, Singapore 117597, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2222-2926","authenticated-orcid":false,"given":"Stephan","family":"Schmid","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5635-3994","authenticated-orcid":false,"given":"Christa","family":"Buechler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9473-3509","authenticated-orcid":false,"given":"Vlad","family":"Pavel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,15]]},"reference":[{"key":"ref_1","first-page":"7","article-title":"Biomarkers for Sepsis: What Is and What Might Be?","volume":"10","author":"Biron","year":"2015","journal-title":"Biomark. Insights"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"628302","DOI":"10.3389\/fmed.2021.628302","article-title":"Sepsis-Pathophysiology and Therapeutic Concepts","volume":"8","author":"Jarczak","year":"2021","journal-title":"Front. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1056\/NEJMcibr1004371","article-title":"Immunotherapy for sepsis\u2014A new approach against an ancient foe","volume":"363","author":"Hotchkiss","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/imcb.12611","article-title":"Lymphopenia in sepsis-an acquired immunodeficiency?","volume":"101","author":"Finfer","year":"2023","journal-title":"Immunol. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1002\/JLB.2MR1119-224R","article-title":"The relevance of soluble CD137 in the regulation of immune responses and for immunotherapeutic intervention","volume":"107","author":"Luu","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4173","DOI":"10.2741\/3521","article-title":"CD137, implications in immunity and potential for therapy","volume":"14","author":"Thum","year":"2009","journal-title":"Front Biosci. (Landmark Ed.)"},{"key":"ref_7","first-page":"245","article-title":"Immunobiology of cancer therapies targeting CD137 and B7-H1\/PD-1 cosignal pathways","volume":"344","author":"Wang","year":"2011","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3482","DOI":"10.1038\/s41375-021-01287-1","article-title":"CD137 (4-1BB) stimulation leads to metabolic and functional reprogramming of human monocytes\/macrophages enhancing their tumoricidal activity","volume":"35","author":"Stoll","year":"2021","journal-title":"Leukemia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"571964","DOI":"10.3389\/fimmu.2020.571964","article-title":"Identification of CD137-Expressing B Cells in Multiple Sclerosis Which Secrete IL-6 Upon Engagement by CD137 Ligand","volume":"11","author":"Wong","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5144","DOI":"10.1128\/IAI.73.8.5144-5151.2005","article-title":"4-1BB (CD137) is required for rapid clearance of Listeria monocytogenes infection","volume":"73","author":"Lee","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1128\/IAI.00115-13","article-title":"CD137 expressed on neutrophils plays dual roles in antibacterial responses against Gram-positive and Gram-negative bacterial infections","volume":"81","author":"Nguyen","year":"2013","journal-title":"Infect. Immun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4218","DOI":"10.4049\/jimmunol.173.6.4218","article-title":"CD137-deficient mice have reduced NK\/NKT cell numbers and function, are resistant to lipopolysaccharide-induced shock syndromes, and have lower IL-4 responses","volume":"173","author":"Vinay","year":"2004","journal-title":"J. Immunol."},{"key":"ref_13","first-page":"A1314","article-title":"Cd137 (4-1bb)-Fc Facilitates Recovery Of Opportunistic Acinetobacter Peumonia In Immunosuppressive Phage Sepsis","volume":"187","author":"Seo","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1006\/cyto.1999.0623","article-title":"Expression of soluble CD137 correlates with activation-induced cell death of lymphocytes","volume":"12","author":"Michel","year":"2000","journal-title":"Cytokine"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Seidel, J., Leitzke, S., Ahrens, B., Sperrhacke, M., Bhakdi, S., and Reiss, K. (2021). Role of ADAM10 and ADAM17 in Regulating CD137 Function. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052730"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/0378-1119(95)00349-B","article-title":"A mRNA variant encoding a soluble form of 4-1BB, a member of the murine NGF\/TNF receptor family","volume":"164","author":"Setareh","year":"1995","journal-title":"Gene"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.jaut.2013.09.002","article-title":"Recombinant soluble CD137 prevents type one diabetes in nonobese diabetic mice","volume":"47","author":"Kachapati","year":"2013","journal-title":"J. Autoimmun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1002\/eji.202149488","article-title":"Soluble CD137 is a novel serum marker of liver cirrhosis in patients with hepatitis C and alcohol-associated disease etiology","volume":"52","author":"Weigand","year":"2022","journal-title":"Eur. J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.3389\/fimmu.2020.01364","article-title":"CD4 T Cell Responses and the Sepsis-Induced Immunoparalysis State","volume":"11","author":"Martin","year":"2020","journal-title":"Front Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1189\/jlb.4HI0616-255R","article-title":"Frontline Science: Defects in immune function in patients with sepsis are associated with PD-1 or PD-L1 expression and can be restored by antibodies targeting PD-1 or PD-L1","volume":"100","author":"Patera","year":"2016","journal-title":"J. Leukoc. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1097\/CCM.0000000000005195","article-title":"Coronavirus Disease 2019 as Cause of Viral Sepsis: A Systematic Review and Meta-Analysis","volume":"49","author":"Karakike","year":"2021","journal-title":"Crit. Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.imlet.2022.07.003","article-title":"Soluble CD137 as a potential biomarker for severe COVID-19","volume":"248","author":"Marques","year":"2022","journal-title":"Immunol. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1172\/JCI128672","article-title":"A conserved intratumoral regulatory T cell signature identifies 4-1BB as a pan-cancer target","volume":"130","author":"Freeman","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yexmp.2011.09.012","article-title":"Admission levels of soluble CD137 are increased in patients with acute pancreatitis and are associated with subsequent complications","volume":"92","author":"Shao","year":"2012","journal-title":"Exp. Mol. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nrgastro.2016.168","article-title":"Liver\u2014Guardian, modifier and target of sepsis","volume":"14","author":"Strnad","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1002\/hep.31644","article-title":"Programmed Death Ligand 1 Is Overexpressed in Liver Macrophages in Chronic Liver Diseases, and Its Blockade Improves the Antibacterial Activity Against Infections","volume":"74","author":"Pose","year":"2021","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s13613-017-0316-z","article-title":"Comparison of diagnostic accuracy in sepsis between presepsin, procalcitonin, and C-reactive protein: A systematic review and meta-analysis","volume":"7","author":"Wu","year":"2017","journal-title":"Ann. Intensive Care"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Agnello, L., Giglio, R.V., Bivona, G., Scazzone, C., Gambino, C.M., Iacona, A., Ciaccio, A.M., Lo Sasso, B., and Ciaccio, M. (2021). The Value of a Complete Blood Count (CBC) for Sepsis Diagnosis and Prognosis. Diagnostics, 11.","DOI":"10.3390\/diagnostics11101881"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.cca.2009.12.011","article-title":"Enhanced levels of soluble and membrane-bound CD137 levels in patients with acute coronary syndromes","volume":"411","author":"Dongming","year":"2010","journal-title":"Clin. Chim. Acta"},{"key":"ref_30","first-page":"1198","article-title":"[Association between CD137 and ischemia-reperfusion injury in patients with acute ST-segment elevation myocardial infarction]","volume":"49","author":"Pan","year":"2021","journal-title":"Zhonghua Xin Xue Guan Bing Za Zhi"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0014-5793(89)80476-4","article-title":"Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes","volume":"242","author":"Castell","year":"1989","journal-title":"FEBS Lett."},{"key":"ref_32","first-page":"113","article-title":"C-reactive protein and bacterial infection in cirrhosis","volume":"27","author":"Pieri","year":"2014","journal-title":"Ann. Gastroenterol."},{"key":"ref_33","first-page":"51","article-title":"Procalcitonin and Liver Disease: A Literature Review","volume":"7","author":"Dong","year":"2019","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e003532","DOI":"10.1136\/jitc-2021-003532","article-title":"Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies","volume":"10","author":"Azpilikueta","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1158\/1078-0432.CCR-21-2918","article-title":"Circulating CD137+ T Cells Correlate with Improved Response to Anti-PD1 Immunotherapy in Patients with Cancer","volume":"28","author":"Zizzari","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"193","DOI":"10.6061\/clinics\/2013(02)OA12","article-title":"Clinical implications of elevated serum soluble CD137 levels in patients with acute coronary syndrome","volume":"68","author":"Yan","year":"2013","journal-title":"Clinics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e24224","DOI":"10.1002\/jcla.24224","article-title":"A comprehensive profiling of soluble immune checkpoints from the sera of patients with non-small cell lung cancer","volume":"36","author":"Peng","year":"2022","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1001\/jama.1995.03520260077036","article-title":"Sepsis, sepsis syndrome, and the systemic inflammatory response syndrome (SIRS). Gulliver in Laputa","volume":"273","author":"Bone","year":"1995","journal-title":"JAMA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17518\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:39:32Z","timestamp":1760132372000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17518"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,15]]},"references-count":39,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242417518"],"URL":"https:\/\/doi.org\/10.3390\/ijms242417518","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,15]]}}}