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Review Antimicrobial Peptides in Saliva and Salivary Glands: Their Roles in the Oral Defense System

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Review Antimicrobial Peptides in Saliva and Salivary Glands: Their Roles in the Oral Defense System Oral Med Pathol 11 (2006) 1 Review Antimicrobial Peptides in Saliva and Salivary Glands: Their Roles in the Oral Defense System Masahiko Mori1, Hiroshi Takeuchi2, Masaru Sato2 and Shinichiro Sumitomo1 1 Department of Oral and Maxillofacial Surgery, 2Department of Oral Pathology, Asahi University School of Dentistry, Gifu, Japan Mori M, Takeuchi H, Sato M and Sumitomo S. Antimicrobial peptides in saliva and salivary glands: their roles in the oral defense system. Oral Med Pathol 2006; 11: 1-17, ISSN 1342-0984 The majority of inflammatory diseases in the oral cavity arise from infections caused by several oral microorganisms inhabiting the biofilms formed on the surfaces of teeth, prosthetic devices, and oral mucosa. Human whole saliva is a mixture of secreted saliva from major and minor salivary glands. In addition, it also contains components derived from crevicular fluid. A number of families of peptides, such as cystatins, histatins, statherins, lipocalins (VEG protein), chromogranins, calprotectins and defensins, are found in whole saliva. In recent years, much attention has been focused on these peptides because they show antimicrobial activity against oral pathogens. These naturally occurring antimicrobial peptides are anticipated to be potent therapeutic agents for oral infectious diseases because the acquision of microbial resitance to antibiotics is one of the most serious problems for antibiotic therapy. The present paper reviews recent findings of studies on antimicrobial peptides found in saliva and salivary glands, with special reference to their nature and function in maintaining oral health. We further discuss the methodology in basic research on antimicrobial peptides as well as the possibility of their clinical use in oral health care science. Key words: antimicrobial peptide, oral health, defense system, saliva, salivary glands Correspondence: Masahiko Mori, Department of Oral and Maxillofacial Surgery 1851-Hozumi, Mizuho, Gifu 501-0296, Japan Phone and Fax: + 81-58-329-1472, E-mail: [email protected] Introduction for microorganisms to adhere firmly onto the surfaces of The mucosal surfaces of the oral cavity are covered teeth and epithelial cells. Biofilms consist not only of mi- with sialoproteins, including immunoglobulins, biologi- croorganisms but also of complex structures of salivary cally active peptides, cytokines and growth factors mucins, food related materials, and exfoliated (sialomucinous coating). Sialomucins are composed keratinocytes. Biofilms also contain leukocytes and mono- mainly of alpha-glycosylated glycoproteins synthesized cytes from gingival crevicular fluid and/or peptides de- from acinar cells in the major and minor salivary glands. rived from these cells. Several pathogenic bacteria in the In addition to the well-known sialoproteins (lysozyme, biofilm produce bacterial toxins and cytokines, and host lactoferrin and peroxidase), human whole saliva contains tissues respond to the stimuli with inflammation. Thus, many other peptides with bactericidal and fungicidal ac- infections in the oral cavity are considered to be protec- tivities (antimicrobial peptides). Antimicrobial peptides tive responses not only for local tissue destructions but were originally discovered in insects with cell-free also for systemic diseases. A new method combining mo- hemolymph, which corresponds to blood in mammals. lecular and immunological techniques has been developed Recently, it has been reported that antimicrobial peptides to investigate biofilm-specific surface protein expression are involved in the innate immunity of mammals and that by Streptococcus sanguis (1), and the results have shown they function in the recognition of pathogens by signal- that surface expression of putative fibronectin and col- ing pathway and effector mechanisms. lagen adhesions is upregulated by biofilm cells. Biofilms Dental biofilms are formed under an oral environ- are resistant to antimicrobial agents. In addition, phago- ment, in which a vast variety of microorganisms become cytic cells cannot phagocytose or kill adhesive bacteria in established and proliferate. Biofilms also make it possible biofilms. Cardiac coronary stenotic artery diseases, as well 2 Mori et al. Antimicrobial peptides in saliva as atherosclerosis caused by periodontal disease-associ- Cystatins are induced in the submandibular (SM) ated bacteria, pose significant health problems. The de- gland of rats treated with β -adrenergic agonists velopment of biofilms containing periodontal disease- (isoproteronol) (9, 10), and high levels of cystatin S mRNA associated bacteria can be prevented by salivary histatins also persist in the rat SM gland (11). Moreover, 5000-fold and cystatins, and thus they may contribute to preven- increase in the cystatin levels were found in isoproter- tion of vascular diseases (2). In order to maintain good enol-treated rats (9), and papain administrated to rats oral health or oral-health-related quality of life (3), new induced cystatins in their salivary glands (12). approaches against oral infectious diseases are urgently Immunohistochemical identification of cystatin has needed. The application of naturally-occurring antimicro- been investigated, and cystatin C and S in the rat SM bial peptides could be a potent program in the prophy- gland showed intense staining in acinar cells but not in laxis and treatment of such oral infectious diseases as ductal cells. Furthermore, isopreterenol-treated rats dental caries, periodontal diseases, peri-implantitis, oral showed high cystatin activity in acinar cells (13). These ulceration, candidiasis, leukoplakia and denture stoma- findings suggest that salivary cystatin could be secreted titis. Almost all such diseases show, at least in some forms, from acinar cells. Rat cystatins in the SM gland are in- features of bacterial or fungal infections. duced by β-adrenergic agonist and correspond to human Although a monograph has been published which cystatin S (14), i.e. LM protein (large mobile protein), a addresses the role of antimicrobial agents in periodontal protein with MW 13,500 that is expressed in both granu- prevention, therapy and maintenance (4), we have cho- lar convoluted tubules (GCT) and acinar cells in normal sen to focus on the key roles of antimicrobial peptides rat SM glands. Upon testosterone administration to rats, from 3 sources: salivary glands, oral epithelial cells, and hypertrophic GCT cells showed marked staining for LM leucocytes or monocytes. We discuss the possibility of the protein, and enlarged acinar cells treated with prolonged utilization of antimicrobial peptides as new preventive isoproterenol were stained most intensely for LM pro- and/or therapeutic agents against oral infectious diseases tein (15, 16). Cystatins (S, SA and SN) found in whole caused by commensal pathogens. This review article also saliva are secreted from the SM-sublingual (SL) glands deals with the immunohistochemical localization of anti- and, to a lesser extent, from the parotid. Henskens et al. microbial peptides from various sources in the oral cav- (17) reported that total cystatin activity in saliva is 5 times ity. higher in SM saliva than in parotid saliva, and cystatins S and C are found in only SM and SL saliva. Cystatins Cystatin levels in inflamed human gingiva range Cystatins are inhibitors of cysteine proteinases, and from 0.21 to 3.82 μg/g tissue as revealed by enzyme- are widly distributed in human tissues and body fluids, linked immunosorbent assay, and cystatin concentrations including saliva. Cystatins are classified into 3 subfami- are decreased in samples with increased pocket depths lies: family I cystatins are represented by cystatin A (stefin (18). Aguirre et al. (19) reported that cystatins in SM-SL A) and cystatin B (stefin B), both of which are non- saliva show a mean value of 129.7 ± 100.9 μg/ml for glycosylated proteins that lack disulfide bonds and con- subjects without periodontal diseases and 92.0 ± 58.1 tain about 100 amino acid residues. Family II cystatins μ g/ml for subjects with periodontal diseases, and that consist of C, D, S, SA, M and F. They are proteins of a there is no statistically- significant difference between single polypeptide chain with disulfide bonds and are these two groups in terms of cystatin level. In contrast, composed of 115-120 amino acids. Family III cystatins Henskens et al. (20) showed that cystatin concentrations are composed of L- and H-kininogens containing in whole saliva of periodontitis patients are significantly glycosylated cytoplasmic proteins with bradykinin moi- higher than those in healthy subjects. It has further been ety. Family III cystatins of high molecular weight are reported that an increase in cystatin levels in whole sa- kininogens and are subdivided into high molecular weight, liva of periodontal disease patients is in part due to in- low molecular weight and tissue kininogens. Cystatins creased salivary gland secretions of both isoform cystatin are distributed in several mammalian species including S and basic cystatin C (17). Cystatins and their synthetic humans, and are also derived from other sources, such as derivatives are capable of blocking bacterial and viral rep- plants, protozoa, bacteria and viruses. Human cystatins lication and inhibiting the chemotactic response, and include cystatins A, B, C, D, S, SA, SN, L-kininogen, and could modulate immune responses in mucosal tissue. H-kininogen in order of their molecular weight (5). These Thus, human salivary cystatin is considered
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