Febrile Temperatures Attenuate IL-1β Release by Inhibiting Proteolytic Processing of the Proform and Influence Th1/Th2 Balance by Favoring Th2 Cytokines

Abstract

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.

Phospholipases C and A2control lysosome-mediated IL-1β secretion: Implications for inflammatory processes

“…The hypothesis that lysosomes are a privileged site for processing is supported by the observation that the lysosomal enzyme cathepsin B may play a role in pro-caspase-1 activation (33). Along this line, febrile temperatures down-modulate IL-1␤ activity by inhibiting processing but not secretion (13,34); it has been proposed that this could be accomplished by influencing cellular compartmentalization so that pro-IL-1␤ does not encounter caspase-1 (34). It is tempting to speculate that this trafficking implies other molecules involved in the regulation of IL-1␤ processing, such as inflammasome components (3,32).…”

Effects of Heat Shock and Hypoxia on Neonatal Neutrophil Lipopolysaccharide Responses: Altered Apoptosis, Toll-Like Receptor-4 and CD11b Expression Compared with Adults

“…Fluctuations in temperature may modulate immune responses [29][30][31] . Down-regulation of TLR-4 expression on monocytes by TNF-␣ is associated with LPS hyporeactivity to NF-B formation whereas IL-6 upregulation of TLR-4 increases responsiveness [32] .…”

Cellular responses to mild heat stress

“…IL-2, interferon (IFN)-g, tumor necrosis factor (TNF)-a] and Th2-cytokine (e.g. IL-5 and IL-13) and thereby to regulate Th1/Th2 cytokine balance is highly temperature dependent and tissue specific [59,156]. For example, when staphylococcal enterotoxin B (SEB)-stimulated whole blood is incubated at 38-42°C, it favors Th2 cytokine production to alter Th1/Th2 cytokine balance [59,156], whereas in situ heated-prostate cancer cells favor Th1-cytokine release of tumor-infiltrating T lymphocytes [157].…”