Fever is generated when pyrogens elevate the hypothalamic thermoregulatory set-point. Which eicosanoid mediates this set-point elevation within the preoptic area?

• A Prostaglandin E2 (PGE2), produced by cyclooxygenase-2 (COX-2) in brain endothelial and microglial cells ✓
• B Leukotriene B4 (LTB4), produced by 5-lipoxygenase in hypothalamic astrocytes
• C Thromboxane A2 (TXA2), acting on TP receptors of warm-sensitive neurons
• D Prostacyclin (PGI2), inhibiting warm-sensitive neurons to reduce heat dissipation

Explanation

Exogenous pyrogens (LPS, other PAMPs) and endogenous pyrogens (IL-1β, IL-6, TNF-α) induce COX-2 expression in brain vasculature, endothelial cells, and perivascular microglia, generating prostaglandin E2. PGE2 binds EP3 receptors on warm-sensitive POAH neurons, reducing their firing rate and thus disinhibiting posterior hypothalamic heat-generation pathways, which shifts the set-point upward (fever). Antipyretics (aspirin, paracetamol) work by inhibiting COX enzymes, reducing PGE2 synthesis. LTB4 (option B), TXA2 (option C), and PGI2 (option D) are not established mediators of fever set-point elevation.

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

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