Abstract
The role of fibroblasts in inflammatory processes and their cross-talk with T cells is increasingly being recognized. Our aim was to explore the capacity of dermal fibroblasts to produce inflammatory chemokines potentially involved in fibrosis occurring in response to contact with polarized human T cells. Our findings indicate that the program of chemokine production by fibroblasts is differentially regulated depending on the T-helper (Th) cell subset used to activate them. Thus, Th1 and Th2 cells preferentially induced production of IFN-γ inducible protein (IP)-10 and IL-8, respectively, whereas monocyte chemoattractant protein (MCP)-1 was equally induced by both subsets at mRNA and protein levels. Neutralization experiments indicated that membrane-associated tumour necrosis factor-α and IL-1 played a major role in the induction of IL-8 and MCP-1 by Th1 and Th2 cells, whereas membrane-associated IFN-γ (present only in Th1 cells) was responsible, at least in part, for the lower IL-8 and higher IP-10 production induced by Th1 cells. The contributions of tumour necrosis factor-α, IL-1 and IFN-α were confirmed when fibroblasts were cultured separated in a semipermeable membrane from living T cells activated by CD3 cross-linking. We observed further differences when we explored signal transduction pathway usage in fibroblasts. Pharmacological inhibition of c-Jun N-terminal kinase and nuclear factor-κB resulted in inhibition of IL-8 mRNA transcription induced by Th1 cells but not that by Th2 cells, whereas inhibition of MEK/ERK (mitogen-activated protein kinase of extracellular signal-regulated kinase/extracellular signal-regulated kinase) and nuclear factor-κB resulted in inhibition of MCP-1 mRNA induced by Th2 but not by Th1 cells. Finally, no distinct differences in chemokine production were observed when the responses to T cell contact or to prototypic Th1 and Th2 cytokines were examined in systemic sclerosis versus normal fibroblasts. These findings indicate that fibroblasts have the potential to participate in shaping the inflammatory response through the activation of flexible programs of chemokine production that depend on the Th subset eliciting their response.
Highlights
Fibroblasts are cells of mesenchymal origin and are principally involved in the generation and maintenance of extracellular matrix
Neutralization experiments indicated that membrane-associated tumour necrosis factor-α and IL-1 played a major role in the induction of IL-8 and monocyte chemoattractant protein (MCP)-1 by Th1 and Th2 cells, whereas membrane-associated IFN-γ was responsible, at least in part, for the lower IL-8 and higher inducible protein (IP)-10 production induced by Th1 cells
Chemokine production by fibroblasts in response to T cell contact We first tested whether human dermal fibroblasts were able to produce IL-8, MCP-1 and IP-10 when activated in a contactdependent manner by polarized T cell clones [36]
Summary
Fibroblasts are cells of mesenchymal origin and are principally involved in the generation and maintenance of extracellular matrix. Chemokines that influence chemotaxis regulate leucocyte homeostasis and recruitment of leucocyte subpopulations at sites of inflammation [9] Their biological functions are broader, comprising relevant roles in virus cell entry, angiogenesis, tumour growth, metastasis formation and fibrosis [10]. In human systemic sclerosis (SSc), MCP-1 mRNA proved to be the most abundant mRNA when bronchoalveolar lavage cells from SSc lung were compared with controls using microarray technology and testing a total of 4507 genes [14]. It is produced in large amounts by SSc skin fibroblasts [13,15,16]. Mice null for CCR2 were resistant to development of lung fibrosis induced by transgenic IL-13 [21] and bleomycin [22]
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