Nitric oxide production is regulated by fever-range thermal stimulation of murine macrophages

As macrophages are often called to function at times of elevated ambient temperature (e.g., during local inflammation or systemic fever), it is possible that their production of critical effector molecules, such as nitric oxide (NO) or inducible NO synthase (iNOS), is sensitive to physiological changes in temperature. To test this possibility, the threshold requirements for production of NO and iNOS in murine peritoneal macrophages maintained under normothermic conditions (37 degrees C) or following mild (fever-range) hyperthermia (39.5 degrees C) were compared. We found that hyperthermia alone had no observable effect on basal NO production or iNOS protein or message. However, although interferon (IFN)-gamma and lipopolysaccharide (LPS) were needed to induce NO at 37 degrees C, we observed that addition of only LPS was sufficient for production of NO if there were a pretreatment at 39.5 degrees C. Further, if IFN-gamma and LPS were given after thermal exposure, a substantial increase in NO and iNOS was observed over that seen using cells kept at normothermic conditions. Macrophages isolated from mice lacking heat shock factor-1 did not attenuate the ability of mild thermal stress to modulate NO production. Reverse transcriptase-polymerase chain reaction data revealed that thermal regulation of iNOS expression is not entirely at the transcriptional level, suggesting possible points of post-transcriptional thermal sensitivity. These data support the concept that altering the thermal microenvironment is an important means by which the host can manipulate macrophage responses. Increases in temperature (e.g., during fever) may function to lower the activation threshold needed for production of effector molecules in times of infection.