Serum amyloid A1 (SAA1) is a prototypic acute phase protein， induced to extremely high levels by physical insults， including inflammation and infection. Human SAA and its NH-terminal part have been studied extensively in the context of amyloidosis. By contrast， little is known about COOH-terminal fragments of SAA. Intact SAA1 chemoattracts leukocytes the G protein-coupled receptor formyl peptide receptor like 1/formyl peptide receptor 2 (FPR2). In addition to direct leukocyte activation， SAA1 induces chemokine production by signaling through toll-like receptor 2. We recently discovered that these induced chemokines synergize with intact SAA1 to chemoattract leukocytes and . Gelatinase B or matrix meta... More
Serum amyloid A1 (SAA1) is a prototypic acute phase protein， induced to extremely high levels by physical insults， including inflammation and infection. Human SAA and its NH-terminal part have been studied extensively in the context of amyloidosis. By contrast， little is known about COOH-terminal fragments of SAA. Intact SAA1 chemoattracts leukocytes the G protein-coupled receptor formyl peptide receptor like 1/formyl peptide receptor 2 (FPR2). In addition to direct leukocyte activation， SAA1 induces chemokine production by signaling through toll-like receptor 2. We recently discovered that these induced chemokines synergize with intact SAA1 to chemoattract leukocytes and . Gelatinase B or matrix metalloproteinase-9 (MMP-9) is also induced by SAA1 during infection and inflammation and processes many substrates in the immune system. We demonstrate here that MMP-9 rapidly cleaves SAA1 at a known consensus sequence that is also present in gelatins. Processing of SAA1 by MMP-9 at an accessible loop between two alpha helices yielded predominantly three COOH-terminal fragments: SAA1(52-104)， SAA1(57-104)， and SAA1(58-104)， with a relative molecular mass of 5，884.4， 5，327.3， and 5，256.3， respectively. To investigate the effect of proteolytic processing on the biological activity of SAA1， we chemically synthesized the COOH-terminal SAA fragments SAA1(52-104) and SAA1(58-104) and the complementary NH-terminal peptide SAA1(1-51). In contrast to intact SAA1， the synthesized SAA1 peptides did not induce interleukin-8/CXCL8 in monocytes or fibroblasts. Moreover， these fragments possessed no direct chemotactic activity for neutrophils， as observed for intact SAA1. However， comparable to intact SAA1， SAA1(58-104) cooperated with CXCL8 in neutrophil activation and migration， whereas SAA1(1-51) lacked this potentiating activity. This cooperative interaction between the COOH-terminal SAA1 fragment and CXCL8 in neutrophil chemotaxis was mediated by FPR2. Hence， proteolytic cleavage of SAA1 by MMP-9 fine tunes the inflammatory capacity of this acute phase protein in that only the synergistic interactions with chemokines remain to prolong the duration of inflammation.
