B. Haslinger et al., Hyaluronan fragments induce the synthesis of MCP-1 and IL-8 in cultured human peritoneal mesothelial cells, CELL TIS RE, 305(1), 2001, pp. 79-86
Human peritoneal mesothelial cells (HMC) play an important role in inflamma
tory processes by their ability to produce various cytokines and chemokines
, such as monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-
8). In this study we investigated the effect of experimentally generated hy
aluronan (HA) fragments, degradation products of the extracellular matrix c
omponent hyaluronan, which accumulate at inflammatory sites, on the express
ion of MCP-1 and IL-8 in cultured HMC. MCP-1 and IL-8 mRNA expression was d
etermined by RNase protection assays, and protein levels in the supernatant
s were measured by enzyme-linked immunosorbent assays. HA fragments with a
molecular mass of approximately 1-7x10(5) daltons upregulate MCP-1 and IL-8
synthesis in HMC dose and time dependently. The effect of HA fragments cou
ld be blocked by Ro31-8220, a specific protein kinase C inhibitor, and by P
D98059, an inhibitor of the mitogen-activated protein kinase/extracellular
signal-regulated kinase pathway. Upregulation of chemokine synthesis was pr
eceded by an increase in NF-kappaB and AP-1 DNA-binding activity, suggestin
g that these transcription factors are activated to increase MCP-1 and IL-8
expression by HA fragments. These data demonstrate that HA fragments marke
dly enhance the mRNA expression and protein synthesis of MCP-1 and IL-8 in
HMC. In concert with previous findings, our observations indicate that enha
nced levels of HA, which are present in the peritoneal cavity of peritoneal
dialysis patients, may account for a locally increased chemokine productio
n.