The hypothesis that IL-1β is a key factor in the pro-inflammatory response to psychological stress is based on several lines of evidence. First, psychological stressors have been demonstrated to increase pro-inflammatory cytokines such as IL-1β and TNFα in blood and brain tissue (Madrigal et al., 2002; O’Connor et al., 2003; Raison et al., 2006). Second, our preliminary studies demonstrate that acute restraint stress first increases IL-1β in the hippocampus, prior to increasing levels of IL-6 and TNFα (unpublished). Moreover, stress increases ATP levels in the hippocampus resulting in P2X7 receptor dependent elevation of IL-1β, and subsequent release of TNFα and IL-6 (unpublished) (Fig. 2). This is similar to neuropathic pain, which also causes an initial induction of IL-1β that is dependent on ATP-P2X7 receptor activation (Nadeau et al., 2011; Whitehead et al., 2010). In contrast, experimental bacterial infection (i.e., LPS) first increases TNFα (Amiot et al., 1997).
