CD156 (ADAM8) is part of the ADAM family of proteins with the catalytic site consensus sequence of metalloprotease and disintegrins. To examine the role of CD156 in vivo, we generated mutant CD156 (eCD156) transgenic mice expressing the ectodomain of CD156 under the control of the α1-antitrypsin (AT) promoter. One of the transgenic mice designated ATMS2-TG18 expressed a 1.84 kb mRNA which was predicted to be a truncated CD156. The expression of the transgenic CD156 mRNA in ATMS2-TG18 mice was abundant in the liver and slight in kidney. Turpentine oil (TO) and lipopolysaccharide (LPS) markedly upregulated the expression. Soluble CD156 (sCD156) was produced constitutively, and increased after the treatment with TO. Casein-induced peritoneal leukocyte infiltration was significantly less extensive in ATMS2-TG18 than non-transgenic mice. The expression of L-selectin in neutrophils (PMN) from peripheral blood leukocytes (PBL) was more strongly downregulated in ATMS2-TG18 than non-transgenic mice, suggesting that L-selectin in PMN from ATMS2-TG18 mice was shed by sCD156. In contrast, oxazolone (Ox)-induced contact hypersensitivity reactions (CHR) were more marked in ATMS2-TG18 than non-transgenic mice. The expression of E-selectin mRNA was detected in inflammatory skin sites from ATMS2-TG18, but not non-transgenic mice, suggesting that sCD156 may activate the endothelial cells and lead to the upregulation of E-selectin. These results suggest that CD156 regulates leukocyte infiltration directly or indirectly.