The development of the pro-inflammatory phenotype in adulthood [33,34]. Other studies examined theAggression and Cytokine Levels in Plasmaassociation between cytokines and aggression in animals. Gene knockout depletion of IL-6 (2/2) in mice resulted in increased aggression compared to control mice [35]. Moreover, in normal mice, over-expression of IL-6 in the brain increases affiliative behavior [35]. These data suggests that at least in mice IL-6 plays a causal role in aggression. Also in mice, IL-1b administration was found to reduce aggressive behavior in a dose-dependent manner supporting a causal relationship with aggression of this cytokine as well [36]. In mice bred for high aggression, IFNc, IL-2 production, and T cell proliferation were higher than in mice bred for low aggression [37]. Interestingly, early life exposure to endotoxin, an immune activator, was found to reduce aggressive behavior in an aggressive strain of mice [38]. Taken together these studies suggest that cytokine expression profile may be a mediator linking experiences in early life to lifespan physical and mental health. Although alterations in the levels of various cytokines have been shown to be associated with human disease and behavioral disorders, the association between cytokine levels and long-term regulation of physical aggression in humans is still unknown. We therefore used two longitudinal cohorts of children to examine whether cytokine levels in blood of young adults associate with their history of childhood physical aggression. To test this hypothesis, we measured an array of 10 inflammatory cytokines in a sample of males who had a history of chronic physical aggression between 6 and 15 years of age and compared them with boys from the same background who followed a normal physical aggression trajectory [2]. Our panel included a mix of five cytokines that were previously associated with human and animal behavioral problems and others whose association with these disorders was unknown.Results Plasma Cytokine Levels are Reduced in the Chronic Physical Aggression (CPA) GroupWe first compared the two groups, controls and chronic physical aggressive (CPA) to identify Title Loaded From File possible confounders (Table 1). They did not differ significantly on age at the two blood samplings, on familial adversity during childhood, on their psychiatric record and on two behavior problems rated by teachers from kindergarten to high school: anxiety and inattention. As expected, a significantly higher proportion of the CPA group had a criminal record by age 24 and reported physical violence at age 21. Thus, the CPA group which was classified during childhood and adolescence maintained the phenotype into adulthood at the time when blood samples were collected. The CPA group also had a higher mean score for teacher rated hyperactivity and opposition between 6 and 15 years. We measured the plasma Title Loaded From File concentration of 10 cytokines using multiplex array-based ELISA at two time points (age 26 and 28) to obtain a reliable cytokine concentration for each subject. As expected, the cytokine concentrations at time 1 were significantly correlated with their concentrations 2 years later (R = 0.554, P = 1.48E-17). Using repeated measure ANOVA, no significant mean differences between times and no interactions with the aggression groups for all the 10 cytokines were revealed after correcting for multiple testing (Bonferoni correction with a #0.005). The analyses were therefore performed on the avera.The development of the pro-inflammatory phenotype in adulthood [33,34]. Other studies examined theAggression and Cytokine Levels in Plasmaassociation between cytokines and aggression in animals. Gene knockout depletion of IL-6 (2/2) in mice resulted in increased aggression compared to control mice [35]. Moreover, in normal mice, over-expression of IL-6 in the brain increases affiliative behavior [35]. These data suggests that at least in mice IL-6 plays a causal role in aggression. Also in mice, IL-1b administration was found to reduce aggressive behavior in a dose-dependent manner supporting a causal relationship with aggression of this cytokine as well [36]. In mice bred for high aggression, IFNc, IL-2 production, and T cell proliferation were higher than in mice bred for low aggression [37]. Interestingly, early life exposure to endotoxin, an immune activator, was found to reduce aggressive behavior in an aggressive strain of mice [38]. Taken together these studies suggest that cytokine expression profile may be a mediator linking experiences in early life to lifespan physical and mental health. Although alterations in the levels of various cytokines have been shown to be associated with human disease and behavioral disorders, the association between cytokine levels and long-term regulation of physical aggression in humans is still unknown. We therefore used two longitudinal cohorts of children to examine whether cytokine levels in blood of young adults associate with their history of childhood physical aggression. To test this hypothesis, we measured an array of 10 inflammatory cytokines in a sample of males who had a history of chronic physical aggression between 6 and 15 years of age and compared them with boys from the same background who followed a normal physical aggression trajectory [2]. Our panel included a mix of five cytokines that were previously associated with human and animal behavioral problems and others whose association with these disorders was unknown.Results Plasma Cytokine Levels are Reduced in the Chronic Physical Aggression (CPA) GroupWe first compared the two groups, controls and chronic physical aggressive (CPA) to identify possible confounders (Table 1). They did not differ significantly on age at the two blood samplings, on familial adversity during childhood, on their psychiatric record and on two behavior problems rated by teachers from kindergarten to high school: anxiety and inattention. As expected, a significantly higher proportion of the CPA group had a criminal record by age 24 and reported physical violence at age 21. Thus, the CPA group which was classified during childhood and adolescence maintained the phenotype into adulthood at the time when blood samples were collected. The CPA group also had a higher mean score for teacher rated hyperactivity and opposition between 6 and 15 years. We measured the plasma concentration of 10 cytokines using multiplex array-based ELISA at two time points (age 26 and 28) to obtain a reliable cytokine concentration for each subject. As expected, the cytokine concentrations at time 1 were significantly correlated with their concentrations 2 years later (R = 0.554, P = 1.48E-17). Using repeated measure ANOVA, no significant mean differences between times and no interactions with the aggression groups for all the 10 cytokines were revealed after correcting for multiple testing (Bonferoni correction with a #0.005). The analyses were therefore performed on the avera.
