Figure 2.

Competitive molecular circuits potentially responsible for the dynamic programing of innate leukocytes. Varying doses of LPS may engage unique TLR4 complexes that may cause intra-cellular pathway switching, leading to either low-grade non-resolving inflammation, or acute resolving inflammation. Super-low-dose LPS selectively activates GSK3 and JNK, while suppressing AKT and ERK. These two branches may also have mutually inhibitory interactions, further fine-tuning cellular inflammatory states. Low- to high-dose LPS potently induces NFκB and MAP kinases, leading to robust inflammatory reactions. On the other hand, low- to high-dose LPS could also trigger the activation of AKT and ERK, which may serve to dampen inflammatory responses. IRAK-1 appears to be critical for both the low-grade inflammation triggered by super-low-dose LPS and the anti-inflammatory responses (e.g., IL-10 expression through ERK activation) activated by high-dose LPS.