Phase-Dependent Roles of E-Selectin during Chronic Contact Hypersensitivity Responses

Tomoyuki Fujita^*, Manabu Fujimoto^*, Takashi Matsushita^*, Yuka Shimada^*, Minoru Hasegawa^*, Yoshihiro Kuwano, Fumihide Ogawa, Kazuhiko Takehara^* and Shinichi Sato^*

From the Department of Dermatology,^* Kanazawa University Graduate School of Medical Science, Kanazawa; the Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo; and the Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

Chronic contact hypersensitivity (CH) models induced by repeatedhapten exposure exhibit chronic dermatitis and immunologicalabnormalities resembling atopic dermatitis. To assess the contributionof endothelial selectins (P- and E-selectins) to cutaneous chronicinflammation, chronic CH responses were assessed in mice lackingP- or E-selectin. Elicitation with oxazolone on the ears ofP-selectin^–/– mice 7 days after the sensitizationinduced a typical delayed-type hypersensitivity response similarto that found in wild-type mice. By contrast, a significantincrease in ear swelling was observed in E-selectin^–/–mice 36 to 48 hours after first elicitation. E-selectin^–/–mice showed augmented P-selectin up-regulation, and administrationof anti-P-selectin monoclonal antibody significantly inhibitedthe enhanced ear response, suggesting that the enhanced ear-swellingresponse in E-selectin^–/– mice resulted from compensatoryincrease in P-selectin expression. In the late phase of chronicCH, acceleration of ear swelling was significantly reduced inboth E- and P-selectin^–/– mice relative to wild-typelittermates. Thus, the loss of P- or E-selectin suppressed inflammatoryresponses during the chronic phase of the chronic models, whereasearly-phase inflammatory responses were exacerbated by E-selectinblockade. Collectively, P- and E-selectins cooperatively regulateCH response, although their roles may be different dependingon the phase of the reaction.