The role of cyclooxygenases in endotoxin- and interleukin-1-induced hypophagia

Endotoxin (lipopolysaccharide, LPS) and interleukin-1 (IL-1) reduce food in take in rodents. Cyclooxygenase (COX) inhibitors have long been known to at tenuate these responses, but recent work has revealed the existence of two distinct isoforms of the enzyme, COX1 and COX2, with different characterist ics and functions. Therefore, we reassessed the COX involvement using inhib itors with different selectivities for COX1 and COX2. Feeding was assessed in nondeprived mice by measuring the intake of sweetened milk in a 30-minut e period, as well as daily food pellet intake. LPS and IL-1 beta consistent ly reduced milk intake. Treatment of the mice with the selective COX1 inhib itor, piroxicam, attenuated the hypophagic responses to IL-1 and LPS. Simil ar results were obtained with diclofenac. The hypophagic responses to LPS a nd IL-1 beta were not affected by the COX2-selective inhibitors nimesulide and NS-398 at doses considered selective for COX2, but were inhibited by hi gher doses. Pretreatment of the mice with aspirin, an irreversible inhibito r of COX1 and COX2, prevented the hypophagic response to IL-1, 16 h, but no t 40 h later. Taken together, these results suggest that COX1 may be the ma jor isozyme involved in the hypophagic responses to LPS and IL-1, but a rol e for COX2 cannot be excluded. We also studied the combination of a COX inh ibitor with the IL-1 receptor antagonist protein. Consistent with earlier r esults, both the IL-1 receptor antagonist (IL-1ra) and indomethacin attenua ted the hypophagic responses to LPS. Combination of the two treatments prod uced additive results almost completely preventing the hypophagic response. Because indomethacin almost completely prevented the hypophagic response t o IL-1, this additivity suggests that there are multiple mechanisms by whic h LPS induces hypophagia. (C) 2000 Academic Press.