Pyrogen

A pyrogen is a substance that induces fever. Pyrogens can be exogenous, such as microbial components including lipopolysaccharide endotoxin from Gram-negative bacteria and other bacterial products, or endogenous, such as cytokines released by the host immune system (notably interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha).

Mechanism of action involves sensing by immune cells of microbial components, leading to the release of pyrogenic cytokines into the bloodstream. These mediators reach the hypothalamus and stimulate the production of prostaglandin E2 via cyclooxygenase enzymes. Prostaglandin E2 raises the hypothalamic set point, triggering heat-generation responses (shivering, increased metabolic rate) and reduced heat loss (vasoconstriction). When pyrogen levels decline, prostaglandin E2 decreases and the body temperature returns toward normal.

Clinical significance encompasses fever as a common response to infection and inflammation. In medical and pharmaceutical settings, pyrogens are of concern because fever can accompany the administration of drugs or contaminated products. Exogenous pyrogens, especially endotoxins, are routinely screened in products using assays such as the Limulus amebocyte lysate (LAL) test or recombinant alternatives; historical methods included the rabbit pyrogen test. Modern testing also employs monocyte activation tests and other in vitro approaches.

Treatment and management focus on controlling fever when appropriate. Antipyretic drugs, including nonsteroidal anti-inflammatory drugs and acetaminophen, reduce fever by inhibiting cyclooxygenase and lowering brain prostaglandin E2 synthesis. Fever remains a balance between host defense advantages and potential risks from elevated temperatures.