ADHESION MOLECULE EXPRESSION ON SKIN ENDOTHELIA IN ATOPIC-DERMATITIS - EFFECTS OF TNF-ALPHA AND IL-4

Background: Atopic dermatitis (AD) is characterized by skin infiltrate s of leukocytes, such as lymphocytes and eosinophils. Objective: To de scribe the mechanisms determining this inflammatory process, we have a nalyzed expression of adhesion molecules and their regulation on skin endothelial cells (ECs). Methods: Expression of adhesion molecules on ECs was analyzed by immunohistochemistry by using Ulex europaeus agglu tin 1 as a pan-endothelial marker. Results: Vascular cell adhesion mol ecule-1 (VCAM-1), E-selectin, and P-selectin were not found in skin of nonatopic individuals, whereas expression of these sur face molecules was observed in nonlesional skin of patients with AD and was even mor e pronounced in lesional skin or after epicutaneous application of aer oallergen, Induction of adhesion molecule expression was examined on b oth macrovascular ECs from human umbilical cord vein (HUVECs) and huma n microvascular ECs (HMEC-1) from skin, TNF-alpha very potently upregu lated adhesion molecule expression in vitro on both EC cell types. To verify the in vivo relevance of TNF-alpha, we performed TNF-alpha stai ning in the skin. TNF-alpha was observed in the dermis of nonatopic sk in, both in chymase-containing mast cells and CD68+ macrophages. The i ncrease in the number of TNF alpha-containing cells was concomitant wi th the increase in adhesion molecule expression in the skin of patient s with AD. IL-4 is supposed to be important in atopic diseases because of its IgE- and VCAM-1-inducing properties. However, IL-4 addition fa iled to induce VCAM-1 expression on HMEC-1, although in the same set o f experiments, a clear induction of VCAM-1 expression by IL-4 on HUVEC s was demonstrated, Flow cytometry revealed the absence of IL-4 recept or alpha-chains on HMEC-1 and their presence on HUVECs, Immunohistoche mistry examination on skin sections showed no binding of the IL-4R alp ha-chain antibodies to ECs. Conclusion: We conclude that adhesion mole cule expression is increased in the skin of patients with AD. Most pro bably, this increased expression is not a (direct) effect of IL-4 on s kin endothelium, but other cytokines, such as TNF-alpha, might be resp onsible for this increased adhesion molecule expression. Continuous ad hesion molecule expression may facilitate T-cell extravasation in a no nantigen-specific manner, thus explaining the presence of increased T- cell numbers in nonlesional skin of patients with AD.