TUMOR-NECROSIS-FACTOR-ALPHA IS PRO-INFLAMMATORY IN NORMAL HUMAN SKIN AND MODULATES CUTANEOUS ADHESION MOLECULE EXPRESSION

Tumour necrosis factor alpha (TNF-alpha) is a potent immunoregulatory cytokine produced by many cutaneous cells, including keratinocytes, ma st cells and Langerhans cells. To explore its potential role in inflam matory skin disease, we have studied immunohistochemically the effects of intradermal recombinant human TNF-alpha (rHuTNF-alpha) on cutaneou s inflammatory cells, adhesion molecules and Langerhans cells in norma l human skin. Volunteers received rHuTNF-alpha 100 U (group A), 5000 U (group B), or 100 U daily for 5 days (group C), and biopsies were tak en 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 si ngle injections of either 100 or 5000 U rHuTNP-alpha this was predomin antly neutrophilic, whereas following multiple injections of 100 U few neutrophils were seen, although many lymphocytes (CD3+ CD4(+)) were p resent. In all groups there was an increase in cells of monocyte/macro phage 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, interce llular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecul e-1 (VCAM-1) in all groups, and adhesion molecule expression by inters titial dermal dendritic cells (ICAM-1 and VCAM-1) and keratinocytes (I CAM-1) was observed. These findings indicate that TNF-alpha is a poten t modulator of cutaneous immune function in vivo, and this central rol e in the cutaneous immune response suggests that TNF-alpha may be an a ttractive target for therapeutic inhibition.