High molar ratios of tumor necrosis factor α (TNF α) soluble receptors I and II to the TNF ligand in human plasma from male veterans with comorbid posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI)

BACKGROUND AND OBJECTIVES: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with chronic inflammation, as inferred from increased, but variable, peripheral levels of cytokines. We sought proof of concept for the notion that peripheral cytokine binding proteins and/or soluble receptors can confound measures of cytokines in those with a history of physical and psychological traumatic exposures. Efforts were focused on one of the major cytokines involved in inflammation, tumor necrosis factor-α (TNF-α). METHODS: We examined blood plasma concentrations of TNF-α, its soluble receptors (TNF-soluble receptors (sR) I and TNFsRII), and C-reactive protein (CRP-1) in a cohort of US Veterans. In a previous study, CRP-1 was shown to be reduced by probiotic anti-inflammatory treatment in this patient cohort. All participants (n = 22) were diagnosed with PTSD and had a history of mild TBI with persistent post-concussive symptoms. Exclusion criteria included medications directly targeting inflammation. RESULTS: Molar concentrations of soluble TNFsRI and II exceeded concentrations of the TNF-α ligand. TNFsRI, but not TNFsRII, was significantly associated with CRP-1 (Spearman Rho correlations = 0.518; p=.016 and 0.365; p = .104, respectively). CONCLUSIONS: TNF soluble receptors may bind to and sequester free TNF-α, suggesting that only measuring ligand concentrations may not provide a fully comprehensive view of inflammation, and potentially lead to inaccurate conclusions. TNFsRI concentration may provide a better estimate of inflammation than TNF-α for those with PTSD and post-acute mTBI with post-concussive symptoms, a hypothesis that invites further testing in larger studies.