Epidermal expression of intercellular adhesion molecule 1 is not a primary inducer of cutaneous inflammation in transgenic mice.

Abstract

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 attai in the transgenic mice exceeded the peak level of ICAM-1 expression induced on nontransgenic mouse keratinocytes in vitro by optimal combinations of interferon y and tumor necrosis factor a 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 transgeneencoded 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 inflammtion. 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 traiMcking and elicit cutaneous inflammation.

Intercellular Adhesion Molecule-1 and Hair Follicle Regression

“…In this study we demonstrate that mouse skin and HFs exhibit a more widespread and much more dynamic constitutive ICAM-1 expression pattern (Figures 1-3) than was previously recognized (Goebeler et al 1990(Goebeler et al ,1994Scheynius et al 1993;Williams and Kupper 1994). In particular, novel physiological and hair cycle-dependent patterns of ICAM-1 expression are identified in defined anatomic skin compartments (Table 1): on selected epidermal keratinocytes (Figure 2A), in the peri-infundibular outer root sheath (piORS) (Figures 2B and 2C), in the hair matrix ( Figure 2D), and in the proximal connective tissue sheath ( Figures 2E-2G) as well as on perifollicular endothelial cells ( Figure 2J).…”

“…Cryosections of mouse skin sections incubated with nonimmune hamster IgG at the same concentration as the primary antibody were used as negative controls. Positive controls included (a) cryosections of murine spleen and thymus, (b) inflamed telogen skin after 3 days of topical dimethylsulfoxide treatment (DMSO; 100%), which causes generalized upregulation of ICAM-1 expression via induction of an acute irritant contact dermatitis, and (c) untreated telogen skin with its well-characterized constitutive, orthotopic ICAM-1 expression on cutaneous blood vessels (Goebeler et al 1990(Goebeler et al ,1994Scheynius et al 1993;Williams and Kupper 1994). The observed antigen distribution was compared to published expression patterns for use as internal positive controls.…”

Cytotoxic T lymphocytes form an antigen-independent ring junction

“…The densities of ICAM-1 that trigger ring junction formation are consistent with levels of ICAM-1 expressed on activated lymphoid and myeloid cells and cytokine-activated nonhematopoietic cells. While ICAM-1 expression alone is not thought to trigger activation of immune or inflammatory responses (29), it is likely that increasing ICAM-1 expression facilitates the effectiveness of T cells' hunting for targets. Consistent with this, ICAM-1 is downregulated by the Kaposi sarcoma K5 protein, contributing to defects in T cell recognition (30).…”

Inflammatory and hyperproliferative skin disease in mice that express elevated levels of the IL-1 receptor (type I) on epidermal keratinocytes. Evidence that IL-1-inducible secondary cytokines produced by keratinocytes in vivo can cause skin disease.

“…Keratinocytes were derived from adult mouse ears using sequential dispase and trypsin digestion (22). Primary cultures were established, split after two days into wells of a 96-well plate and then grown for 24 h in medium containing various concentrations of recombinant murine IL-1 ␣ (kind gift of Dr. P. Lomedico, Hoffman LaRoche, Nutley, NJ).…”