Can inflammatory signaling raise ferritin and sustain lipid mediator imbalance?

Systemic inflammation drives a complex biochemical network where surrogate acute-phase markers and lipid signaling pathways mutually reinforce chronic pathology.

Molecular drivers of ferritin elevation

• Cytokine-mediated transcription: Inflammatory cytokines, specifically IL-6, IL-1, and TNF-α, directly stimulate ferritin synthesis, overriding classic iron-dependent translational repression.
• Pathway activation: IL-6 triggers the JAK-STAT3 pathway, while TNF-α and IL-1 activate NF-κB. These pathways drive the transcription of the ferritin heavy-chain (FTH) subunit independent of cellular iron levels.
• Translational bypass: NF-κB targets the "acute-phase box" translational enhancer on the 5' untranslated region of ferritin transcripts, allowing active translation to proceed even when iron-regulatory proteins would normally suppress it.

Eicosanoid-driven immune feedback loops

• Immune cell amplification: Pro-inflammatory eicosanoids, such as leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), signal through GPCRs to recruit and activate key immune cells, including neutrophils and T lymphocytes.
• Pathological feedback: Activated immune cells release additional eicosanoids, establishing a reciprocal feedback loop. Specifically, leukotriene D4 (LTD4) signaling upregulates COX-2 expression via calcium, calcineurin, and NFAT signaling pathways.
• Class-switching failure: Persistent NF-κB activation maintains concurrent COX-2 and 5-LOX expression. This blocks the physiological transition from pro-inflammatory lipid mediators to specialized pro-resolving mediators (SPMs), trapping the microenvironment in a chronic, self-perpetuating lipid imbalance.

Bottom line

• Inflammatory signaling elevates ferritin as an acute-phase reactant via JAK-STAT3 and NF-κB pathways, while concurrent eicosanoid signaling drives a pathological, self-amplifying immune feedback loop that blocks resolution and perpetuates chronic lipid mediator imbalance.