👤 Kate Ryan Kuhlman

Psychosocial stress has been linked to myriad mental and physical health conditions. Stress-induced changes to functioning of the immune system is a plausible mechanism in this association. Psychosocial stress is a well-established contributor to immune dysregulation, though the extant literature to date falls short of addressing the role of distal relative to contemporary stress in immune function, particularly as they relate to distinctions between innate and adaptive immunity. The present study directly addressed this knowledge gap by characterizing vertically-integrated markers of immune functioning as a function of both recent chronic stress during adolescence and childhood adversity. In the present study, childhood adversity (before age 10) and recent psychosocial stressors (past 6 months) were characterized via semi-structured clinical interviews among 127 adolescent girls (aged 13-17; 31 % Black, 38 % Hispanic, 32 % NHW) who have all measures included in this report. Vertically-integrated markers of immune activity were also collected: an a priori subset of immune-related genes using genome-wide transcriptional profiling, an 11-plex of circulating cytokines (IL-6, TNF-α, IL-10, IL-8, IFN-γ, IL-1β, IL-1α, IL-27, MCP-1, IL-12p70, IP-10), and systemic inflammation (C-reactive protein; CRP). The association between recent chronic stress and intracellular immune outcomes differed based on childhood adversity. Genome-wide transcriptional profiling implicated myeloid lineage cells, specifically monocytes and dendritic cells, in differential patterns of gene expression among childhood adversity-exposed youth in the context of chronic stress. These differential patterns were also reflected in expression of proinflammatory genes and CRP such that among adolescents without exposure to childhood adversity, more recent chronic stress was associated with less proinflammatory gene expression, b = -0.45 (SE = 0.22), p = 0.04, 95 %CI [-0.87, -0.02], and somewhat higher CRP, b = 0.62 (SE = 0.35), p = 0.08, 95 %CI [-0.07, 1.31], while among adolescents with exposure to childhood adversity, more recent chronic stress was not associated with any immune activity markers. However, these patterns among circulating markers did not survive corrections for multiple comparisons. Immune adaptation in the context of chronic stress may indicate plasticity to environmental demands that conserves biological resources, which may be a source of resilience that is negatively impacted by childhood adversity. Show less

Acetaminophen (APAP) hepatotoxicity is protected by S-adenosyl-l-methionine (SAMe) treatment 1hour (h) after APAP in C57/Bl6 mice. This study examined protein carbonylation as well as mitochondrial and cytosolic protein adduction by 4-hydroxynonenal (4-HNE) using mass spectrometry (MS) analysis. Additional studies investigated the leakage of mitochondrial proteins and 4-HNE adduction of these proteins. Male C57/Bl6 mice (n=5/group) were divided into the following groups and treated as indicated: Veh (15ml/kg water, ip), SAMe (1.25mmol/kg, ip), APAP (250mg/kg), and SAMe given 1h after APAP (S+A). APAP toxicity was confirmed by an increase (p<0.05) in plasma ALT (U/l) and liver weight/10g body weight relative to the Veh, SAMe and S+A groups 4h following APAP treatment. SAMe administered 1h post-APAP partially corrected APAP hepatotoxicity as ALT and liver weight/10g body weights were lower in the S+A group compared the APAP group. APAP induced leakage of the mitochondrial protein, carbamoyl phosphate synthase-1 (CPS-1) into the cytosol and which was reduced in the S+A group. SAMe further reduced the extent of APAP mediated 4-HNE adduction of CPS-1. MS analysis of hepatic and mitochondrial subcellular fractions identified proteins from APAP treated mice. Site specific 4-HNE adducts were identified on mitochondrial proteins sarcosine dehydrogenase and carbamoyl phosphate synthase-1 (CPS-1). In summary, APAP is associated with 4-HNE adduction of proteins as identified by MS analysis and that CPS-1 leakage was greater in APAP treated mice. SAMe reduced the extent of 4-HNE adduction of proteins as well as leakage of CPS-1. Show less