During fever, the set-point of the hypothalamic thermostat is elevated. Which cytokine is the MOST potent endogenous pyrogen and what is its immediate mediator of set-point elevation at the hypothalamus?
- A TNF-alpha; acts directly on POAH neurons via p55 receptor without a lipid mediator
- B IL-1beta and IL-6; stimulate hypothalamic (POAH) COX-2 to produce PGE2, which acts on EP3 receptors in POAH to raise the temperature set-point ✓
- C Interferon-gamma; stimulates AVP release which acts as the hypothalamic temperature signal
- D IL-8; increases brain temperature via direct heating of hypothalamic blood
Explanation
IL-1beta and IL-6 (along with TNF-alpha) are the principal endogenous pyrogens. They act on brain endothelial cells and perivascular microglia surrounding the preoptic area/anterior hypothalamus (POAH) to induce COX-2 expression, increasing local PGE2 synthesis. PGE2 diffuses into the POAH and binds EP3 receptors on thermoregulatory neurons, inhibiting the warm-sensitive neurons that drive heat dissipation, effectively raising the thermal set-point. The body then responds to the new higher set-point with heat conservation (vasoconstriction, shivering) until actual core temperature matches the elevated set-point. Aspirin and NSAIDs reduce fever by inhibiting COX enzymes, reducing PGE2 synthesis. AVP has antipyretic (not pyrogenic) effects.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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