Pyrogens such as IL-1β and IL-6 raise the thermoregulatory set-point in the preoptic area of the hypothalamus. Which is the FINAL intracellular mediator that raises the set-point by inhibiting warm-sensitive neurons?

• A Interleukin-1β directly binding IL-1R on warm-sensitive neurons, opening TRPV1 channels to raise set-point
• B Tumour necrosis factor-alpha (TNF-α), acting via NFκB in hypothalamic neurons to transcribe new thermosensory proteins
• C Nitric oxide, diffusing across the blood-brain barrier and activating guanylate cyclase in hypothalamic neurons to raise set-point
• D Prostaglandin E2 (PGE2), acting via EP3 receptors on warm-sensitive neurons to inhibit them through Gi-linked reduction of cAMP ✓

Explanation

Circulating or brain-generated PGE2 is the final mediator of fever. Pyrogenic cytokines (IL-1β, IL-6, TNF-α) induce PGE2 synthesis (via COX-2) in brain endothelial cells and perivascular microglia; PGE2 diffuses to the preoptic area and binds EP3 receptors (Gi-coupled) on warm-sensitive inhibitory neurons, reducing cAMP, inhibiting their firing, and thereby disinhibiting heat-production pathways—raising the set-point. This is why NSAIDs (COX inhibitors) and paracetamol reduce fever. Cytokines do not directly cross the BBB efficiently enough to act centrally, and TNF-α/NFκB transcription is too slow for fever onset kinetics.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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