Increased CD40 expression in skin fibroblasts from patients with systemic sclerosis (SSc): role of CD40‐CD154 in the phenotype of SSc fibroblasts

Abstract

Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology that is characterized by tissue fibrosis, which may result from the activation of lesional fibroblasts exhibiting excessive production of extracellular matrix components. However, it has yet to be determined how SSc fibroblasts are activated. CD40 is a cell surface molecule expressed on various cells that is important for the response to activated T cells through CD154. CD40 mRNA was found to be constitutively expressed in both SSc and normal fibroblasts by reverse transcription PCR. Expression of CD40 protein was increased on SSc fibroblasts compared to normal fibroblasts as measured by flow cytometry. Ligation of CD40 by recombinant human CD154 (0.5–2 μg/ml) resulted in increased production of IL‐6, IL‐8, and monocyte chemoattractant protein‐1 in SSc fibroblasts in a dose‐dependent manner, whereas these phenomena were not shown in normal fibroblasts even with the addition of CD154. CD80, a costimulatory molecule, was also induced on SSc fibroblasts by CD40 ligation. In the present study, our findings suggest the possibility of a cell‐mediated response between fibroblasts and T cells in the lesional skin of SSc patients. Since it is suggested that the CD40‐CD154 system may play a crucial role in the aberrant production of immune mediators by SSc fibroblasts, blockage of CD40‐CD154 may be a novel therapeutic strategy for SSc.

New developments in the pathogenesis of systemic sclerosis

“…In addition, it has direct effects on fibroblasts and induces fibroblast proliferation [29] and expression of IL-6 [30]. T cells also may interact with fibroblasts via CD154/CD40 ligation to increase production of pro-fibrotic cytokines IL-6, and MCP-1 [31]. However, TH1 (producing IFNg) and to a lesser degree TH2 (producing IL-4) cells can inhibit collagen production by fibroblasts via cell -cell contact involving membrane-associated TNFa [32].…”

An investigation of the inflammatory cytokine and chemokine network in systemic sclerosis

“…Importantly, chemokines and their receptors have been implicated through human, animal and in vitro studies as being involved in the pathogenesis of SSc. In particular, chemokines such as CCL2, CCL5, CCL7 and CXCL8 have been implicated in the initiating phase and in the perpetuation of the inappropriate fibroblast activation and concomitant extracellular matrix deposition that characterise this disease 3–5. This therefore highlights the chemokine/chemokine receptor system as a potential therapeutic target in SSc.…”

Chemokines and Chemokine Receptors in Scleroderma

“…Expression of CD40 was increased on scleroderma fibroblasts compared with normal fibroblasts [46]. Ligation of CD40 by CD40L resulted in increased production of IL-6, IL-8 and CCL2 in scleroderma fibroblasts, but not in normal fibroblasts [46]. Moreover, the combination of IL-4 and ligation of CD40 on the surface of fibroblasts has synergistic effects in stimulating fibroblast proliferation [47].…”

“…Interaction between CD40 on fibroblasts and CD40 ligand (CD40L) on immune cells such as the T cells and mast cells can result in fibroblast activation. Expression of CD40 was increased on scleroderma fibroblasts compared with normal fibroblasts [46]. Ligation of CD40 by CD40L resulted in increased production of IL-6, IL-8 and CCL2 in scleroderma fibroblasts, but not in normal fibroblasts [46].…”