Tumour necrosis factor alpha is pro-inflammatory in normal human skin and modulates cutaneous adhesion molecule expression

Abstract

Tumour necrosis factor alpha (TNF-alpha) is a potent immunoregulatory cytokine produced by many cutaneous cells, including keratinocytes, mast cells and Langerhans cells. To explore its potential role in inflammatory skin disease, we have studied immunohistochemically the effects of intradermal recombinant human TNF-alpha (rHuTNF-alpha) on cutaneous inflammatory cells, adhesion molecules and Langerhans cells in normal human skin. Volunteers receive rHuTNF-alpha 100 U (group A), 5000 U (group B), or 100 U daily for 5 days (group C), and biopsies were taken at 6 h (groups A and B), or 6 h after the final injection (group C). An inflammatory cell infiltrate developed in all cases: following single injections of either 100 or 5000 U rHuTNF-alpha this was predominantly neutrophilic, whereas following multiple injections of 100 U few neutrophils were seen, although many lymphocytes (CD3+, CD4+) were present. In all groups there was an increase in cells of monocyte/macrophage lineage (CD36+). TNF-alpha induced a dose- and time-dependent decrease in CD1a+ epidermal Langerhans cell numbers and an increase in dermal CD1a+ cells, suggesting migration of Langerhans cells away from the epidermis. TNF-alpha induced endothelial E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in all groups, and adhesion molecule expression by interstitial dermal dendritic cells (ICAM-1 and VCAM-1) and keratinocytes (ICAM-1) was observed. These findings indicate that TNF-alpha is a potent modulator of cutaneous immune function in vivo, and this central role in the cutaneous immune response suggests that TNF-alpha may be an attractive target for therapeutic inhibition.

Inflammatory skin disease in transgenic mice that express high levels of interleukin 1 alpha in basal epidermis.

“…However, these findings are consistent with data from injection of IL-1 (11) or TNF (25) into normal human skin, either of which may result in recruitment of many macrophage-like cells. It seems likely that the persistent secretion of IL-1 into the dermis of these animals results in an adhesion molecule and secondary cytokine profile that results preferentially in the accumulation of monocytic cells.…”

Cutting Edge: C-C Chemokine Receptor 6 Is Essential for Arrest of a Subset of Memory T Cells on Activated Dermal Microvascular Endothelial Cells Under Physiologic Flow Conditions In Vitro

“…Our data, however, suggest a surprisingly dominant role for CCR6 and LARC in the acute arrest of mTC to activated dermal endothelium. Although ours is an vitro study, the proteins acutely expressed by TNF-␣-stimulated HDMEC in vitro closely parallel those expressed in vivo when human subjects were injected with TNF-␣ intradermally (25). Moreover, a recent report demonstrated that protein expression of CCR6 and chemotactic sensitivity to LARC are up-regulated in the T cells of psoriatic patients (15), which lends support to the possible importance of CCR6 in vivo.…”

cis-Urocanic Acid Initiates Gene Transcription in Primary Human Keratinocytes

“…2). TNF-␣ has been shown to cause depletion of epidermal Langerhans cells and recruitment of macrophages into the dermis, which are important events in the modulation of alloantigen presentation in human skin (47). The immunosuppressive effects of cis-UCA may be partially mediated via TNF-␣, because anti-TNF-␣ treated or TNF-␣ receptor knockout mice show a reduced cis-UCA induced suppression of the CHS response (9,11).…”