Fig. 5.

Proposed mechanism of the role in HPSE in stimulating the production of cytokines necessary for macrophage activation. By binding to TLR2 or TLR4, HPSE can stimulate the inhibition of p105, causing the release of Tpl2 and downstream ERK activation. ERK signaling results in IL-1β production. Activation of TLR2/4 can stimulate p38, JNK, and NF-κB signaling via an Myd88-dependent formation of a protein complex. Downstream signaling results in the synthesis of MCP-1, IL-6, IL-1, TNF-α, and MIP-2. Alternatively, the binding of HPSE to TLR4 in a TRAM- and TRIF-dependent mechanism which results in activation of PI3K and subsequently Akt. Akt stimulates GSK-3, further bolstering JNK signaling, and the IKK complex, activating NF-κB signaling