Proteoglycans (PGs) are complex glycohydrates, which are composed of core proteins and glycosaminoglycans and widely distributed in connective tissues and on the cell surface of mammalian tissues. We investigated the effect of PG extracted from salmon cartilage on cytokine responses to stimulation with heat-killed Escherichia coli (HKEC) in a mouse macrophage cell line, RAW264.7. PG exhibited the suppression of tumor necrosis factor-a production compared with chondroitin 4 sulfate (C4S) and chondroitin 6 sulfate (C6S). PG also revealed the up-regulation of interleukin-10 production. HKEC-induced Toll-like receptor 4 (TLR4) and inducible nitric oxide synthase expression was dose-dependently suppressed by treatment with PG, C4S or C6S, and the PG showed the strongest suppressive effect among 3 compounds. Only PG dramatically up-regulated the expression of signal transducer and activator of transcription 3 (STAT3), and the phosphorylation of STAT3 in mouse macrophages. Our results suggested that the novel interaction might exist between the extracellular matrix and immune system. (c) 2006 Elsevier Inc. All rights reserved.