Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2

Background: Cyclooxygenases (COX)-1 and -2 are key mediators of the inflammatory response in the central nervous system. Since COX-2 is inducible by inflammatory stimuli, it has been traditionally considered as the most appropriate target for anti-inflammatory drugs. However, the specific roles of COX-1 and COX-2 in modulating a neuroinflammatory response are unclear. Recently, we demonstrated that COX-1 deficient mice show decreased neuroinflammatory response and neuronal damage in response to lipopolysaccharide (LPS). Methods: In this study, we investigated the role of COX-2 in the neuroinflammatory response to intracerebroventricular-injected LPS (5 mu g), a model of direct activation of innate immunity, using COX-2 deficient (COX-2(-/-)) and wild type (COX-2(+/+))mice, as well as COX-2(+/+) mice pretreated for 6 weeks with celecoxib, a COX-2 selective inhibitor. Results: Twenty-four hours after LPS injection, COX-2(-/-) mice showed increased neuronal damage, glial cell activation, mRNA and protein expression of markers of inflammation and oxidative stress, such as cytokines, chemokines, iNOS and NADPH oxidase. Brain protein levels of IL-1 beta, NADPH oxidase subunit p67(phox), and phosphorylated-signal transducer and activator of transcription 3 (STAT3) were higher in COX-2(-/-) and in celecoxib-treated mice, compared to COX-2(+/+) mice. The increased neuroinflammatory response in COX-2(-/-) mice was likely mediated by the upregulation of STAT3 and suppressor of cytokine signaling 3 (SOCS3). Conclusion: These results show that inhibiting COX-2 activity can exacerbate the inflammatory response to LPS, possibly by increasing glial cells activation and upregulating the STAT3 and SOCS3 pathways in the brain.