Abstract
BackgroundInterleukin-1 beta converting enzyme (ICE, caspase 1) is a cysteine protease that processes immature pro-IL-1β into active mature IL-1β. IL-1β is a pro-inflammatory cytokine that mediates many of the physiological and behavioral responses to inflammation. Genetic deletion of ICE has previously been shown to prevent some negative physiologic responses to lipopolysaccharide (LPS)-induced inflammation.MethodsHere we used a preclinical murine model to test the hypothesis that ICE is necessary for development of depression-like behaviors following intracerebroventricular (ICV) treatment with LPS. Adult male ICE knockout (ICE KO) and congenic wild-type C57BL/6 J (WT) mice were administered LPS either ICV at 100 ng/mouse or intraperitoneally (IP) at 830 μg/kg body weight or an equal volume of saline as controls. Mice were monitored up to 48 h after treatment for both sickness and depression-like behaviors.ResultsLPS given ICV induced a loss of body weight in both WT and ICE KO mice. This sickness response was similar between WT and ICE KO mice. As expected, LPS administered ICV increased immobility in the forced swim test (FST) and decreased sucrose preference in WT mice but no change in either of these two depression-like behaviors was observed in ICE KO mice. Expression of TNF-α and CD11b in brain was lower in ICE-KO mice at 24 h following ICV administration of LPS compared to WT mice. In contrast, when LPS was given systemically, sickness response, depression-like behaviors, and expression of these genes were similar between the two strains of mice.ConclusionsThese findings indicate that ICE plays a specific role in depression-like behavior induced by a central inflammatory stimuli even though it is not required when LPS is administered systemically.
Highlights
Interleukin-1 beta converting enzyme (ICE, caspase 1) is a cysteine protease that processes immature pro-IL-1β into active mature IL-1β
Sickness responses were similar in wild-type C57BL/6 J (WT) and IL-1β-converting enzyme (ICE) KO mice following central LPS injection LPS administered ICV decreased body weight of both WT and ICE knockout (ICE KO) mice (Table 1) over the 24-h period following treatment
We examined expression of Interleukin 10 (IL-10) and IL-1 receptor antagonist (IL-1RA) within the brain to determine if ICE deletion leads to increased expression of anti-inflammatory genes (Figure 2b)
Summary
Interleukin-1 beta converting enzyme (ICE, caspase 1) is a cysteine protease that processes immature pro-IL-1β into active mature IL-1β. IL-1β is a pro-inflammatory cytokine that mediates many of the physiological and behavioral responses to inflammation. IL-1β plays a prominent role in neurodegenerative processes [9,15] and has recently been identified for its role in murine models of depression-like behavior [10,16]. In agreement with these preclinical models, evidence from human studies indicates higher cerebral spinal fluid IL-1β levels in patients suffering from acute depression [17]. IL-1β plays a prominent role in brain during inflammation as first evidenced by experiments that demonstrated IL-1β-induced activation of hypothalamic-pituitary-adrenal axis and stress responses [25,26,27]. Targeting of ICE represents a possible alternative therapeutic route to target IL-1β
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