c-Rel is a thermoregulatory knob that fine-tunes NF-κB signaling

Thermal regulation is a mechanism for warm-blooded animals to maintain homeostasis against ambient temperature stress. Also, core body temperature rises with fever, an integral part of host responses to infection. Although responses to heat or cold shock have been described, little is understood about how physiological temperature variations affect inflammatory responses. We tracked real-time responses of NF-κB RelA and c-Rel transcription factors to inflammatory and pyrogenic cytokines TNF-α or IL-1β using endogenous knock-in reporter cells in temperatures ranging from 24°C to 40°C. Quantitative live-cell imaging showed that c-Rel signaling, but not RelA, increases with rising temperature. Computational modeling and transcriptomic analysis indicate that the divergent signaling behaviors of these canonical NF-κB subunits cannot be explained solely by accelerated biochemical reactions in higher temperatures. Rather, cytokine receptor-proximal adaptors are likely to amplify c-Rel signaling for precise analog behaviors. The temperature-sensitivity of c-Rel has broad implications for inflammatory cascades in elevated temperatures.