GM-CSF, IL-1-ALPHA, IL-1-BETA, IL-6, IL-10, ICAM-1 AND VCAM-1 GENE-EXPRESSION AND CYTOKINE PRODUCTION IN HUMAN DUODENAL FIBROBLASTS STIMULATED WITH LIPOPOLYSACCHARIDE, IL-1-ALPHA AND TNF-ALPHA

The role of mucosal fibroblasts in intestinal inflammatory reactions i s not known. In this study, we demonstrate that fibroblasts grown from histologically normal human duodenal biopsy tissues expressed mRNA ge nes for granulocyte-macrophage colony-stimulating factor (GM-CSF), IL- 1 alpha, IL-1 beta, IL-6, IL-8, IL-10, intercellular adhesion molecule -1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) when stimul ated with lipopolysaccharide (LPS) or IL-1 alpha. The increased mRNA e xpression of GM-CSF, IL-1 alpha, IL-1 beta, IL-6 and IL-8 in response to IL-1 alpha and LPS stimulation was time- and dose-dependent. In con trast, IL-10 was weakly expressed when fibroblasts were stimulated wit h LPS, IL-1 alpha or tumour necrosis factor-alpha (TNF-alpha), but the expression was enhanced in the presence of cycloheximide combined wit h optimal concentrations of LPS, IL-1 alpha or TNF-alpha. IL-1 alpha w as a more potent stimulator than LPS for GM-CSF, IL-6, IL-8 and IL-10 expression, but not for IL-1 alpha and IL-1 beta. Increased GM-CSF, IL -6 and IL-8 gene expression was associated with the production of cyto kine proteins in culture supernatant, but IL-1 alpha and IL-1 beta rem ained undetectable. Dexamethasone suppressed both gene expression and protein production of GM-CSF, IL-6 and IL-8 when fibroblasts were expo sed to IL-1 alpha. TNF-alpha stimulated the release of GM-CSF, IL-6 an d IL-8 and, combined with IL-1 alpha, cytokine production was enhanced synergistically. Finally, both LPS and IL-1 alpha up-regulated ICAM-1 and VCAM-1 gene expression. These findings implicate duodenal fibrobl asts in the initiation and/or regulation of intestinal inflammation.