From IL-6 production to IL-6R buffering: a unified IL-6-IL-6R framework for immune homeostasis during viral infection.

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 IL6 and IL6R may influence distinct but interconnected layers of IL-6 regulation. The intronic IL6 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 IL6R 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 IL6R 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.