Abstract
The acute phase response is a hallmark of all inflammatory reactions and acute phase reactants, such as C-reactive protein (CRP) and serum amyloid A (SAA) proteins, are among the most useful plasma and serum markers of inflammation in clinical medicine. Although it is well established that inflammatory cytokines, mainly interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) induce SAA in the liver, the biological functions of elicited SAA remain an enigma. By the classical multi-step protein purification studies of chemotactic factors present in plasma or serum, we discovered novel chemokines and SAA1 fragments, which are induced during inflammatory reactions. In contrast to earlier literature, pure SAA1 fails to induce chemokines, an ascribed function that most probably originates from contaminating lipopolysaccharide (LPS). However, intact SAA1 and fragments thereof synergize with CXC and CC chemokines to enhance chemotaxis. Natural SAA1 fragments are generated by inflammatory proteinases such as matrix metalloproteinase-9 (MMP-9). They mediate synergy with chemokines by the interaction with cognate G protein-coupled receptors (GPCRs), formyl peptide receptor 2 (FPR2) and (CC and CXC) chemokine receptors. In conclusion, SAA1 enforces the action of many chemokines and assists in local leukocyte recruitment, in particular, when the concentrations of specifically-induced chemokines are still low.