Epidermal expression of intercellular adhesion molecule 1 is not a primary inducer of cutaneous inflammation in transgenic mice.
Keratinocytes at sites of cutaneous inflammation have increased expression of intercellular adhesion molecule 1 (ICAM-1), a cytokine-inducible adhesion molecule which binds the leukocyte integrins LFA-1 and Mac-1. Transgenic mice were prepared in which the expression of mouse ICAM-1 was targeted to basal keratinocytes by using the human K14 keratin promoter. The level of constitutive expression attained in the transgenic mice exceeded the peak level of ICAM-1 expression induced on nontransgenic mouse keratinocytes in vitro by optimal combinations of interferon gamma and tumor necrosis factor alpha or in vivo by proinflammatory stimuli such as phorbol 12-myristate 13-acetate. In vitro adhesion assays demonstrated that cultured transgenic keratinocytes were superior to normal keratinocytes as a substrate for the LFA-1-dependent binding of mouse T cells, confirming that the transgene-encoded ICAM-1 was expressed in a functional form. However, the high level of constitutive ICAM-1 expression achieved on keratinocytes in vivo in these transgenic mice did not result in additional recruitment of CD45+ leukocytes into transgenic epidermis, nor did it elicit dermal inflammation. Keratinocyte ICAM-1 expression also did not potentiate contact-hypersensitivity reactions to epicutaneous application of haptens. The absence of a spontaneous phenotype in these transgenic mice was not the result of increased levels of soluble ICAM-1, since serum levels of soluble ICAM-1 were equal in transgenic mice and controls. We conclude that elevated ICAM-1 expression on keratinocytes cannot act independently to influence leukocyte trafficking and elicit cutaneous inflammation.
Williams
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IR
Division of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Kupper
T S
TS
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004731:Endotoxins / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D005091:Exons; D015870:Gene Expression; D013006:Growth Hormone / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000096:biosynthesis*; D007438:Introns; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism*; D007633:Keratins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D015183:Restriction Mapping; D012867:Skin / Q000276:immunology*
D017931:DNA Primers; D004731:Endotoxins; D018799:Intercellular Adhesion Molecule-1; D007633:Keratins; D013006:Growth Hormone