Does IL-6 increase hepcidin and ferritin?

Inflammatory states characterized by elevated interleukin-6 (IL-6) alter systemic iron regulation, driving cellular iron sequestration and elevating biomarker levels like ferritin.

Molecular and cellular mechanisms

• JAK/STAT3 Signaling: IL-6 binds to the gp130 receptor complex on hepatocytes, activating the JAK/STAT3 pathway. Phosphorylated STAT3 translocates to the nucleus and binds to the HAMP promoter, triggering robust transcription of the iron-regulatory hormone hepcidin.
• Ferroportin Degradation: Systemic hepcidin binds directly to ferroportin, the sole cellular iron exporter on macrophages, hepatocytes, and enterocytes. This interaction induces ferroportin phosphorylation, ubiquitination, internalization via clathrin-coated pits, and subsequent lysosomal degradation, halting iron release.

Intracellular storage and ferritin synthesis

• Iron Sequestration: Restricting cellular iron export prevents efflux, trapping recycled iron within the reticuloendothelial system. This expanded intracellular iron pool induces the synthesis of ferritin to safely store the sequestered iron.
• Acute-Phase Reactant Induction: Independent of the hepcidin-ferroportin axis, IL-6 directly stimulates ferritin synthesis as a primary acute-phase reactant. This dual action—intracellular trapping combined with direct cytokine stimulation—significantly elevates both intracellular and serum ferritin levels.

Bottom line

• Bottom line: IL-6 increases hepatic hepcidin production via JAK/STAT3 signaling, which degrades ferroportin and traps iron intracellularly. This sequestration, combined with the direct induction of ferritin as an acute-phase reactant, drives the elevated ferritin levels characteristic of inflammatory states.