Summary
We investigated the extent to which fibroblasts isolated from diverse tissues differ
in their capacity to modulate inflammation by comparing the global gene expression
profiles of cultured human fibroblasts from skin, acute and chronically inflamed synovium,
lymph node and tonsil. The responses of these fibroblasts to TNF-α, IFN-γ and IL-4
stimulation were markedly different, as revealed by hierarchical cluster analysis
and principal component analysis. In the absence of exogenous cytokine, syn-ovial
and skin fibroblasts exhibited similar patterns of gene expression. However their
transcriptional profiles diverged upon treatment with TNF-α.This proved to be biologically
relevant, as TNF-α induced the secretion of different patterns and amounts of IL-6,
IL-8 and CCL2 (MCP-1) in the two fibroblast types. Co-culture of skin or synovial
fibroblasts with synovial fluid-derived mononuclear cells provided further evidence
that these transcriptional differences were functionally significant in an ex vivo setting. Interestingly, the transcriptional response of skin fibroblasts to IL-4
converged with that of TNF-α-treated synovial fibroblasts, suggesting resident tissue
fibroblasts and their blood-borne precursors may be imprinted by inflammatory cytokines
that are characteristic of different tissues. Our data supports the concept that fibroblasts
are heterogeneous, and that they contribute to the tissue-specificity of inflammatory
reactions. Fibroblasts are therefore likely to play an active role in the persistence
of chronic inflammatory reactions.
This publication was partially financed by Serono Foundation for the Advancement of
Medical Science.
Part of this paper was originally presented at the 2nd International Workshop on New
Therapeutic Targets in Vascular Biology from February 6-9, 2003 in Geneva, Switzerland.
Keywords
Inflammation - fibroblast - chemokine - leucocyte - human
