Abstract

Recently accumulating information suggests the existence of endogenous TLR4 candidate including hyaluronan fragments, HMGB1, Tenascin, saturated fatty acids, S100A8, etc. (reviewed in [1]). We have added one more candidate SAA3 (serum amyloid A3) [2]. In our experimental metastasis assay, we subcutaneously inject tumor cells that never reach the lungs, which we call pre-metastatic lungs (pre-metastatic phase) [3]. Then we purposely inject labeled tumor cells via the tail vein and count their numbers in the lungs (metastatic phase). A cDNA microarray screening for up-regulated genes in pre-metastatic lungs between tumor-bearing and non-bearing mice gave both S100A8 and SAA3 in the top 50 genes [2, 4]. Surface plasmon resonance analysis of TLR4/MD-2 complex purified from baculovirus and S100A8 or SAA3 purified from mammalian cells provided direct evidence for binding. TLR is a well-studied pattern recognition receptor working as a sensor for bacterial endotoxin or lipopolysaccharide (LPS). S100A8 was initially identified in the synovial fluid of rheumatoid arthritis patients and is one of the members of well-conserved EF-hand Ca2+-binding protein family [5, 6]. SAA3 belong to the SAA family of acute phase reactant [7]. SAA1 and SAA2 are generated in liver in response to inflammation and integrated into HDL (high density lipoprotein). SAA3 is produced extra-hepatically, such as in myeloid cells and endothelial cells. We have shown that S100A8 induces SAA3 expression with promoter activation by two- to fourfolds [2]

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