Human healthy skin is continuously exposed to bacteria,but is particularly resistant to the common gut bacrerium Escherichia coli. We show here that keratinocyte secrete,as the main E.coli-killing compound,the s100 protein psoriasin in vitro and in vivo in a site-dependent way. In vivo treatment of human skin with antibodies to psoriasin inhibited its E.coli-killing properties. Psoriasin was induced in keratinocytes in vitro and in vivo by E.coli,indicating that its focal expression in skin may derive from local microbial induction. Zn2+ -saturated psoriasin showed diminished antimicrobial activity,suggesting that Zn2+ sequestration could be a possible antimicrobial mechanism. Thus,psoriasin may be key to the resistance of skin against E.coli.