Human peritoneal fibroblasts are a potent source of neutrophil-targeting cytokines: a key role of IL-1beta stimulation.

Polymorphonuclear leukocyte (PMN) infiltration is a cardinal feature of peritonitis. CXC chemokine ligands 1 and 8 (CXCL1 and CXCL8), and the cytokine granulocyte colony-stimulating factor (G-CSF) are the key mediators of PMN accumulation. Increasing evidence points to an important role of human peritoneal fibroblasts (HPFB) in the response of the peritoneum to infection. We have examined the synthesis of PMN-targeting cytokines by HPFB exposed to intraperitoneal milieu as represented by peritoneal dialysate effluent (PDE) from patients undergoing peritoneal dialysis. PDE obtained during peritonitis, but not during infection-free periods, significantly increased production of CXCL1, CXCL8, and G-CSF by HPFB. The effect was largely blocked by antibodies to interleukin-1beta (IL-1beta), whereas neutralization of tumor necrosis factor-alpha (TNFalpha) had no major effect. Similar pattern of inhibition was observed when HPFB were exposed to conditioned media from endotoxin-stimulated peritoneal macrophages. Significance of IL-1beta stimulation was further shown in experiments with recombinant cytokines. Compared with TNFalpha, exposure of HPFB to recombinant IL-1beta resulted in a much higher release of PMN-targeting cytokines. The assessment of mRNA degradation revealed that the IL-1beta-induced transcripts of CXCL1, CXCL8, and G-CSF were more stable compared with those induced by TNFalpha. These data indicate that HPFB can be a significant source of PMN-targeting cytokines when stimulated with IL-1beta in the inflamed peritoneum.