Febrile temperatures attenuate IL-1β release by inhibiting proteolytic processing of the proform and influence Th1/Th2 balance by favoring Th2 cytokines

We investigated possible feedback mechanisms of febrile temperatures on LPS- and staphylococcal enterotoxin B (SEB)-induced cytokine release in human whole blood. LPS-induced IL-1β release was inhibited at temperatures >38°C, whereas intracellular proIL-1β formation as well as the release of other cytokines except IL-18 were only attenuated above 42°C, indicating that febrile temperatures impair the proteolytic processing of proIL-1β. This attenuated processing is not due to either heat inactivation of caspase-1 or structural changes in proIL-1β produced at higher temperatures. Instead, we propose that febrile conditions change cytosolic compartmentation or trafficking, so that synthesized proIL-1β cannot encounter caspase-1. Febrile temperatures also influenced Th1/Th2 cytokine balance. We observed a 3-fold increase in the Th2-cytokines IL-5 and IL-13 and a reduction to 15% of the Th1-cytokine IL-2 when SEB-stimulated whole blood was incubated at 40°C compared with 37°C. These results indicate that fever limits the production of the fever-inducing IL-1β and also influences the adaptive immune response, favoring Th2 cytokine production.