Tumour necrosis factor-alpha but not interferon-gamma is the main inducer of inducible protein-10 in skin fibroblasts from patients with atopic dermatitis

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Abstract
Inducible protein (IP)-10 belongs to the CXC chemokine subfamily and acts through the CXCR3 receptors that attract T lymphocytes. Keratinocytes are thought to be the main cell source of this chemokine in the skin, but other sources need to be elucidated. To determine whether skin fibroblasts, besides keratinocytes, are able to produce IP-10 and the possible involvement of these cells in pathogenesis of atopic dermatitis (AD). We studied the production pattern of IP-10 in dermal fibroblasts obtained from healthy donors, AD patients and in the HaCaT cell line (normal human keratinocytes) used as control. We stimulated fibroblasts after the sixth and seventh passage with tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-4, and by means of reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay analysis detected the production pattern of IP-10. To determine whether a different pattern of production of IP-10 by fibroblasts corresponds to the level of this chemokine in the plasma of patients with AD, we also checked the plasma IP-10 levels in 33 AD patients and 10 healthy donors. The pattern of chemokine production between dermal fibroblasts and HaCaT cells was different. The main inducer of IP-10 in fibroblasts was TNF-alpha, whereas IFN-gamma was the main inducer of IP-10 in HaCaT cells. We demonstrate that fibroblasts from AD patients have higher IP-10 expression and are more sensitive to TNF-alpha stimulation compared with healthy controls. Consequently, IP-10 levels in plasma of AD patients were higher than in healthy donors. Skin fibroblasts could be an important source of IP-10. TNF-alpha is the main inducer of IP-10 by skin fibroblasts, but not IFN-gamma or IL-4. The increased level of IP-10 in the plasma of patients with AD could be connected with increased activity of skin fibroblasts.