Distinct Roles for Cyclooxygenases 1 and 2 in Interleukin-1-Induced Behavioral Changes

Abstract

Interleukin-1 (IL-1) induces hypophagia, which can be reduced by cyclooxygenase (COX) inhibitors. Earlier studies with COX knockout (COXko) mice suggested that COX2 was more important for hypophagia than COX1. However, behavioral responses occur long before COX2 is induced. Hypophagia was assessed in mice by measuring the intake of sweetened milk in a brief period. The intake was reduced within 30 min after intraperitoneal injection of IL-1␤ and was depressed for about 2 h. When milk intake was measured 30 to 40 min after IL-1␤, COX1ko mice showed an attenuated response, whereas COX2ko mice responded more like wild-type animals. By contrast, 90 to 120 min after IL-1␤ COX1ko mice responded normally, whereas COX2ko mice showed only small responses. The COX2-selective inhibitor, celecoxib, failed to alter the response to IL-1␤ 30 min after administration, but low doses antagonized the effects of IL-1␤ at 90 to 120 min. The COX1-selective inhibitor, SC560, attenuated both the early and late responses, but a larger effect at 30 min than at 90 min suggested a role for COX1 at the earlier time. These results suggest that shortly after IL-1␤ administration, COX1 is the major enzyme involved in the reduction of milk intake, whereas at later times COX2 is more important, paralleling its induction. Celecoxib also attenuated the milk intake response observed 2 h after lipopolysaccharide (LPS), and the reductions of food pellet intake and body weight induced by IL-1␤ and LPS in the subsequent 24 h, suggesting that the role of COX2 may be more significant biologically than that of COX1.

Effects of interleukin-1 and endotoxin in the forced swim and tail suspension tests in mice

“…These time points were chosen based on previous behavioral, endocrine and neurochemical studies. When mice were presented with sweetened milk, the response to IL-1 appeared around 15-20 min, and persisted for approximately 2 h, with the maximum response between 30 and 90 min (Swiergiel and Dunn, 2002). The increase in plasma corticosterone occurred over a similar time period with a peak around 2 h, closely paralleling the brain noradrenergic response, while the increases in tryptophan and in serotonin metabolism occurred between 90 min and 4 h (Dunn, 1988(Dunn, ,1992.…”

Effects of cytokines and infections on brain neurochemistry

“…However, such inhibitors are less effective against the LPS-induced behavioral changes [183,187], and have only small effects on the behavioral changes associated with influenza virus infection [183]. Interestingly, the early responses to IL-1 and LPS involve the COX1 isozyme, whereas COX2 is involved in the later phases of the response [188]. The latter parallels COX2 induction in brain endothelia (Dunn, Swiergiel and Quan, unpublished observations).…”

The role of biomarkers in evaluating human health concerns from fungal contaminants in food

“…Given DON's capacity to elicit systemic pro-inflammatory cytokines and cause inflammation in vivo, it has been hypothesised that COX-2 may be important for DON's ability to cause anorexia and subsequent growth suppression in vivo (154) . COX-2, along with microsomal PGE synthase-1 (mPGES-1), are two enzymes responsible for converting arachidonic acid into PGE 2 during an inflammatory response (155) and COX-2 has been shown to serve a function in anorexia caused by systemic inflammation (156,157) . Indeed, DON induces COX-2 gene expression in vitro (RAW 264·7 murine macrophages) and in vivo (158,159) , though the recent use of mPGES-1 knockout mice suggests that a PGE 2 -independent mechanism causes DON-induced anorexia (152) .…”