Tumor necrosis factor (TNF) receptor type 1 (p55) is a main mediator for TNF‐α‐induced skin inflammation

Abstract

Tumor necrosis factor α (TNF-α) is a pleiotropic proinflammatory cytokine that elicits a large number of biological effects, including inflammatory and immuno-regulatory responses. Biological activities of TNF-α are mediated by two distinct TNF receptors, p55 type 1 receptor (TNFR1) and p75 type 2 receptor (TNFR2). To determine the role of TNF-α in the induction of inflammatory responses in the skin, gene-targeted mutant mice lacking either TNFR1 or TNFR2 were painted with irritant chemicals. Both phenol and croton oil painting onto the ears induced less inflammation in TNFR1(−) mice than normal and TNFR2(−) mice. Intradermal injection of TNF-α (0.2–200 ng for 3 days) into the ear induced less inflammation in TNFR1(−) mice than in normal mice. TNFR2(−) mice developed a normal inflammatory reaction to high doses of TNF-α (20–200 ng for 3 days), while they showed minimal reactivity to low doses of TNF-α (0.2–2 ng for 3 days). TNF-α is known to trigger the release of a series of other cytokines and to induce the expression of cell adhesion molecules, thus contributing to the development of inflammation. The levels of protein and mRNA for interleukin (IL)-6 were elevated in keratinocytes from normal as well as TNFR2(−) mice after treatment with TNF-α, while keratinocytes from TNFR1(−) mice did not show any up-regulation of IL-6. TNF-α induced intercellular adhesion molecule (ICAM)-1 expression in the keratinocytes from normal and TNFR2(−) mice, but not in those from TNFR1(−) mice. These results indicate that TNFR1 is critical for induction of skin inflammation by TNF-α.