{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:46:19Z","timestamp":1791413179206,"version":"4.3.3"},"reference-count":71,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":2194,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>IL-18 is a member of the IL-1 cytokine family, and elevated blood IL-18 concentrations associate with disease activity in macrophage activation syndrome (MAS) and poor clinical outcomes in severe inflammatory and septic conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Although recent investigations provide mechanistic evidence for a contribution of IL-18 to inflammation and hyperinflammation in sepsis and MAS, we sought to study regulatory mechanisms underlying human IL-18 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Samples from in vivo and in vitro endotoxin rechallenge experiments, patients with inflammatory disease, and isolated human monocytes treated with various stimulants and drugs were tested for cytokine gene and protein expression. Serum IL-18 expression with or without JAK\/STAT inhibition was analyzed in two MAS mouse models and in a patient with recurrent MAS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Peripheral blood and monocytic IL-18 expression escaped LPS-induced immunoparalysis. LPS-stimulated primary human monocytes revealed specific IL-18 expression kinetics controlled by IFN\u03b1\/\u03b2 signaling. JAK\/STAT inhibition or IFN\u03b2 neutralization during LPS stimulation blunted cytokine expression. Similarly, microtubule-destabilizing drugs abrogated LPS-induced IL18 expression, but this effect could be fully reversed by addition of IFN\u03b1\/\u03b2. Ex vivo analysis of inflammatory disease patients\u2019 whole blood revealed strong correlation of type I IFN score and IL18 expression, whereas JAK\/STAT inhibition strongly reduced IL-18 serum levels in two MAS mouse models and in a patient with recurrent MAS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data indicate that IL-18 (but not IL-1\u03b2) production from human monocytes requires cooperative Toll-like receptor and IFN\u03b1\/\u03b2 signaling. Interference with IFN\u03b1\/\u03b2 expression or signaling following JAK\/STAT inhibition may control catastrophic hyperinflammation in MAS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201903-0659oc","type":"journal-article","created":{"date-parts":[[2019,11,11]],"date-time":"2019-11-11T12:34:03Z","timestamp":1573475643000},"page":"526-539","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":59,"title":["Synergistic Signaling of TLR and IFN\u03b1\/\u03b2 Facilitates Escape of IL-18 Expression from Endotoxin Tolerance"],"prefix":"10.1093","volume":"201","author":[{"given":"Emely","family":"Verweyen","sequence":"first","affiliation":[{"name":"Department of Pediatric Rheumatology and Immunology, University Children\u2019s Hospital, M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Holzinger","sequence":"additional","affiliation":[{"name":"Department of 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