{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T14:10:28Z","timestamp":1790086228619,"version":"4.0.1"},"reference-count":168,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013302","name":"King Abdullah International Medical Research Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013302","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Interleukin-6 (IL-6) is a pleiotropic cytokine that coordinates innate and adaptive immunity and maintains tissue homeostasis during infection and inflammation. Although transient IL-6 production is essential for host defense, dysregulated or sustained IL-6 activity contributes to immunopathology across infectious and inflammatory diseases. Dengue virus (DENV) infection provides an important context in which this balance may become disrupted. Elevated circulating IL-6 levels are associated with endothelial dysfunction, vascular leakage, coagulopathy, and severe dengue; however, the mechanisms regulating IL-6 bioavailability, signaling duration, and resolution remain incompletely understood. Genetic variation within\n                    <jats:italic>IL6<\/jats:italic>\n                    and\n                    <jats:italic>IL6R<\/jats:italic>\n                    may influence distinct but interconnected layers of IL-6 regulation. The intronic\n                    <jats:italic>IL6<\/jats:italic>\n                    rs2069843 and promoter rs1800795 variants have been associated with dengue susceptibility and severity in some populations and proposed to influence IL-6 expression, although their effects are not consistently replicated. In contrast, the functional\n                    <jats:italic>IL6R<\/jats:italic>\n                    rs2228145 (Asp358Ala; also known as rs8192284) variant enhances shedding of membrane-bound IL-6R and increases circulating soluble IL-6R (sIL-6R), thereby altering the extracellular context of IL-6 signaling. Importantly, increased sIL-6R may either facilitate IL-6 trans-signaling or contribute to extracellular buffering depending on the availability of soluble gp130 (sgp130). Experimental evidence for a dendritic cell-derived sIL-6R buffering system provides a physiological framework for understanding this regulation during acute viral infection. In this review, we integrate evidence from human genetics, cytokine biology, receptor signaling, and dengue immunopathogenesis to propose a unified, hypothesis-driven framework of IL-6 regulation. We conceptualize IL6 variants as potential modifiers of IL-6 production, whereas\n                    <jats:italic>IL6R<\/jats:italic>\n                    rs2228145 may modify soluble receptor buffering capacity and the extracellular distribution of IL-6. We further hypothesize that the dynamic balance among IL-6 production, sIL-6R availability, and sgp130-mediated neutralization, together with receptor abundance and ligand-receptor kinetics, may determine the intensity and duration of IL-6 activity more effectively than circulating IL-6 concentration alone. This framework provides experimentally testable hypotheses for understanding inter-individual variation in IL-6 homeostasis and dengue disease progression and may inform future biomarker development and precision immunomodulatory strategies.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1955147","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:57:34Z","timestamp":1790085454000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From IL-6 production to IL-6R buffering: a unified IL-6-IL-6R framework for immune homeostasis during viral infection"],"prefix":"10.3389","volume":"17","author":[{"given":"Ashraf S.","family":"Yousif","sequence":"first","affiliation":[{"name":"Department of Infectious Disease Research, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health 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