# CYTOTOXIC MECHANISMS IN CUTANEOUS DISEASE

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 1992 · $209,299

## Abstract

Cytokine-induced expression of ICAM-1 (Intercellular Adhesion Molecule-1,
CD54) on the surface of epidermal keratinocytes is a prerequisite for
leukocyte/keratinocyte attachment and immunologic cytotoxicity of
keratinocytes.  We have found that the epidermis is a stratified
immunologic environment, especially with respect to ICAM-1 induction.  We
propose that the epidermal basal keratinocyte is particularly susceptible
to immunologic cytotoxicity because of enhanced ICAM-1 induction by
cytokines.  In this grant we will focus on individual and
differentiation-dependent variation in induction of ICAM-1 expression in
keratinocytes.  We will identify "high" and "low" responders to TNF-a and
IFN-g by analysis of cell surface ICAM-1 expression and distribution by
FACS and ELISA. We will determine if cultured keratinocytes from these
donors show significant differences in cytokine receptor distribution,
density or function, and whether these receptors can be induced by
cytokine priming.  We will also analyze the effects of keratinocyte
differentiation on these receptor variables and on ICAM-1 MRNA induction
using Northern and slot blot analysis.  Individual and
differentiation-dependent differences in release of TNF-a in
keratinocytes will also be characterized by FACS, immunoblot and Northern
blot analysis, to further characterize the high TNF-a responder
phenotype.  We will also determine if IL-1a is an inducer of ICAM-1 in
basal keratinocytes and whether icIL-1ra is responsible for low IL-l
responses in more differentiated keratinocytes.  Finally, we will verify
that enhanced ICAM-1 expression determines the level of immunologic
cytotoxicity of keratinocyte targets.  We will further test this
hypothesis in a prototype of basal keratinocyte cytotoxicity:
photosensitive lupus erythematosus.  Using keratinocytes from lupus
patients, we propose to show that TNF-a induction of expression of ICAM-1
and Ro/SSA or La/SSB antigens on the cell surface of keratinocytes
renders these cells susceptible to cytotoxic damage by anti Ro/SSA or
La/SSA antibodies and/or cellular effectors.  These experiments address
the control and functional significance of the stratified expression of
the adhesion molecule ICAM-1 in the epidermis-a most critical step in
keratinocyte cytotoxicity.  This work is crucial in our long-term study
of the cytotoxic mechanisms of skin diseases.

## Key facts

- **NIH application ID:** 3155407
- **Project number:** 2R01AR026427-12A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **SAM.gov UEI:** MW8JHK6ZYEX8
- **Principal Investigator:** DAVID A. NORRIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $209,299
- **Award type:** 2
- **Project period:** 1980-01-01 → 1996-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3155407

## Citation

> US National Institutes of Health, RePORTER application 3155407, CYTOTOXIC MECHANISMS IN CUTANEOUS DISEASE (2R01AR026427-12A1). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3155407. Licensed CC0.

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