Defence molecules in intestinal innate immunity against bacterial infections Lars Eckmann Purpose of review Antimicrobial proteins are key effector molecules of innate immunity. The review discusses recent progress in understanding the function of these host defence molecules in intestinal physiology. Recent findings All antimicrobial proteins can inhibit or kill bacteria in vitro, but differ markedly in their localization, regulation, and additional activities. a-Defensins are expressed constitutively in human neutrophils and small intestinal Paneth cells, where they require proteolytic processing and signal-induced release to be active in the intestinal lumen. Neutrophil-derived a- defensins can inhibit angiogenesis. Cryptdin-related sequence peptides form a subfamily of a-defensins in murine but not human Paneth cells that can form covalently linked heterodimers, leading to increased structural diversity and antimicrobial target range. Human b-defensins (hBD) are expressed prominently in epithelial cells of the intestinal tract and other organs exposed to the environment. Their epithelial production is either constitutive, as exemplified by hBD-1, or strongly inducible, as shown for hBD-2,-3, and -4. Human cathelicidin, LL-37/hCAP18, is expressed constitutively by differentiated epithelial cells in the colon and stomach, but not the small intestine, as well as neutrophils and mast cells. It has multiple functions beyond its antimicrobial activity, including promotion of angiogenesis, attraction of leukocyte subsets, and activation of chemokine secretion. Angiogenins are a family of host defence-related ribonucleases, of which at least one is secreted by murine Paneth cells. Summary The differential expression of diverse antimicrobial proteins in the gastrointestinal tract suggests that they occupy distinct functional niches in mucosal innate defence, which holds promise for pharmacological exploitation of their antimicrobial properties Keywords cathelicidins, defensins, intestine, mucosal immunology Curr Opin Gastroenterol 21:147—151. ª 2005 Lippincott Williams & Wilkins. Department of Medicine, University of California, San Diego, La Jolla, California, USA This work was supported by NIH grants RR17030, AI56075, and DK35108. Correspondence to Lars Eckmann, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA Tel: +1 858 534 0683; fax: +1 858 822 6454; e-mail: leckmann@ucsd.edu Current Opinion in Gastroenterology 2005, 21:147—151 Abbreviations CRAMP cathelin-related anti-microbial peptide CRS cryptdin-related sequence hBD human b-defensin HD human defensin HNP human neutrophil peptide ª 2005 Lippincott Williams & Wilkins. 0267-1379 Introduction The gastrointestinal tract is constantly in contact with an abundant commensal bacterial microbiota and is exposed frequently to food- and waterborne microbes, yet most of the body is entirely free of microbes. This remarkably effective barrier is achieved through multiple layers of physical separation and chemical host defence. The in- nate immune system plays a central role in controlling and eliminating intestinal microbes, whereas adaptive im- munity is not required for basic survival or proper intesti- nal function in mammals under normal circumstances. This review focuses on recent observations and insights in the area of defence molecules as effectors of innate immu- nity in the intestinal tract. Space constraints preclude dis- cussion of the exciting new developments in the area of innate microbial sensor molecules, including the NOD proteins and Toll-like receptors. The reader is referred to excellent recent reviews on this subject [1–6]. Mammals produce an array of molecules with activity against bacteria and other microbes, which can be divided roughly into antimicrobial proteins and inorganic disinfec- tants such as nitric oxide and hydrogen peroxide. Two ma- jor families of antimicrobial proteins have been identified, defensins and cathelicidins. Defensins Defensins are small (2–6 kDa) cationic peptides with an- timicrobial activity. They have three characteristic pairs of intramolecular disulfide bonds and a b-sheet structure, and can kill bacteria through membrane disruption. Based on the arrangement and spacing of disulfide bonds, defen- sins are divided into two major groups, a-defensins and b-defensins. a-Defensins and cryptdin-related sequences It has been known for some time that humans and mice produce multiple defensins, but their exact number and diversity has remained unclear. The completion of the human and mouse genome sequencing projects has set 147