Beta2 integrin/ICAM-1 adhesion molecule interactions in cutaneous inflammation and tumor promotion

The beta2 integrin (CD 18/CD 11 a, b, c) family of proteins mediateadherence of leukocytes to vascular endothelium and the associated ligand,intercellular adhesion molecule-1 (ICAM-1; CD 54), interacts with beta2integrin proteins to allow transendothelial migration of leukocytes intosites of inflammation. The present study examines the function of theseproteins in a murine model of acute cutaneous inflammation inducedfollowing topical application of 12-O- tetradecanoylphorbol-13-acetate(TPA) to the dorsal epidermis of SENCAR mice and in a model of skinmultistage carcinogenesis. At 24 h following topical application of TPA tothe dorsal epidermis of mice, dermal leukocytes expressed higher levels ofbeta2 integrin protein compared with the lower levels of beta2 integrinprotein expression by peripheral blood leukocytes. ICAM-1 protein waslocalized to epidermal keratinocytes and vascular endothelium inTPA-treated skin and to proliferating papilloma cells. Intravenous (i.v.)injection of either 50 microg anti-beta2 integrin antibody alone or incombination with anti-ICAM-1 antibody significantly inhibited bothTPA-stimulated neutrophil infiltration into the dermis (P < 0.001) andmyeloperoxidase (MPO) activity (P < 0.03 anti-beta2 integrin antibody; P< 0.01 anti- beta2 integrin + ICAM-1 adhesion molecule antibodies), buthad no effect on TPA-induced epidermal hyperplasia. In addition, injectionof either anti-ICAM-1 adhesion molecule antibody alone (P < 0.004) or incombination with anti-beta2 integrin antibody (P < 0.001) significantlyinhibited TPA-induced production of 7,8-dihydroxy-2'-deoxyguanosine (8-OHdG) immunoreactive proteins by epidermal keratinocytes. Beta2integrin/ICAM-1 adhesion molecules work in concert to regulate migration,retention and functional activation of leukocytes within the dermis duringTPA-induced skin inflammation and within stromal tissue of papillomas thatform during multi-stage carcinogenesis. Agents that inhibit thesereceptor/ligand interactions may be useful in defining the roles ofspecific cell populations in cutaneous inflammation and multistagecarcinogenesis and may also have potential as anti-promoting andanti-progression agents.