Fig. 9.
Hypothetical mechanism of sepsis-related immune suppression in macrophages and possible mechanism of therapeutic efficacy of interferon (IFN) β–based on previous publications and the current study. (A) Lipopolysaccharide (LPS) signaling of naive cells. Toll-like receptor (TLR) 4 signaling initially activates TLR4-related intracellular signaling including the p65-p50 nuclear factor-κB–mediated activation of downstream signaling for proinflammatory mediators including IFNβ. IFNβ binds to type 1 IFN receptor in an autocrine manner to activate the Janus kinase-signal transducer and activator of transcription pathway for the downstream expression of IFN-stimulated genes that encode IL-6. (B) LPS-tolerant cells. Concurrently, suppressors of cytokine signaling, such as suppressor of cytokine signaling 3 (Socs3) and p21, were expressed and attenuated subsequent TLR4 signaling. A p21-induced shift of the nuclear factor-κB subunits from p65-p50 to p50-p50 inhibits the nuclear translocation of nuclear factor-κB to bound to nuclear factor-κB–inducible genes, including IFNβ. These phenomena are termed M2 polarization. (C) Prophylactic IFNβ might prime macrophages and concomitantly induce Socs and p21 genes to induce macrophages irresponsive to TLR4 signaling (i.e., M2 polarization), which will be compromised to subsequent overwhelming infection (B). (D) Therapeutic IFNβ might reactivate downstream IFNβ signaling to increase the expression of inflammatory cytokines/chemokines and elicit the bactericidal capacity of the host. See text for further details.