Yanling Jiang

Chemokines, a Family of Chemotactic Cytokines:

Chemokines are low-molecular-weight proteins that stimulate recruitment of leukocytes. They are secondary pro-inflammatory mediators that are induced by primary pro-inflammatory mediators such as interleukin-1 (IL-1) or tumor necrosis factor (TNF). The physiologic importance of this family of mediators is derived from their specificity. Unlike the classic leukocyte chemo-attractants, which have little specificity, members of the chemokine family induce recruitment of well-defined leukocyte subsets. Thus, chemokine expression can account for the presence of different types of leukocytes observed in various normal or pathologic states. There are two major chemokine sub-families based upon the position of cysteine residues, i.e., CXC and CC. All members of the CXC chemokine sub-family have an intervening amino acid between the first two cysteines; members of the CC chemokine sub-family have two adjacent cysteines. As a general rule (with some notable exceptions), members of the CXC chemokines are chemotactic for neutrophils, and CC chemokines are chemotactic for monocytes and a small sub-set of lymphocytes. This review discusses the potential role of chemokines in inflammation and focuses on the two best-characterized chemokines, monocyte chemoattractant protein-1 (MCP-1), a CC chemokine, and interleukin-8 (IL-8), a member of the CXC chemokine sub-family.

Periodontal disease: bacterial virulence factors, host response and impact on systemic health.

Teeth are coated with a biofilm that contains periodontal pathogens. Pathogens express virulence factors which enable them to invade and replicate within epithelial cells and to invade the underlying connective tissue. This stimulates production of prostaglandins and cytokines that induce tissue loss. In addition, these bacteria have the potential to modulate the course of systemic diseases such as atherosclerosis and to contribute to low birthweight and preterm labor.

Interleukin-1 and tumor necrosis factor receptor signaling is not required for bacteria-induced osteoclastogenesis and bone loss but is essential for protecting the host from a mixed anaerobic infection.

Bacterial infection causes significant morbidity, mediated in part by the up-regulation of inflammatory cytokines. Cytokine induction is thought to stimulate osteolysis in conditions such as periodontal disease and otitis media. To establish the relative importance of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in mediating the response to a mixed anaerobic infection, we used an in vivo model in which the dental pulp was inoculated with six anaerobic pathogens, in mice with functional deletions of receptors to IL-1 (IL-1RI(-/-)), TNF (TNFRp55(-/-)-p75(-/-)), or both (TNFRp55(-/-)-IL-1RI(-/-)). Polymorphonuclear and mononuclear phagocyte recruitment occurred to the greatest extent in TNFRp55(-/-)-IL-1RI(-/-) mice, and to a lesser extent in IL-1RI(-/-) or TNFRp55(-/-)-p75(-/-) mice, and the least in wild-type mice, demonstrating that recruitment of these phagocytes is not dependent on IL-1 or TNF receptor signaling. A similar pattern was observed for bacterial penetration into host tissue. Because it had recently been reported that TNF played a critical role in mediating lipopolysaccharide-induced bone loss, we anticipated that mice with targeted deletions of TNFRp55(-/-) would have reduced osteoclastogenesis. Surprisingly, osteolytic lesion formation was greatest in animals lacking TNF and/or IL-1 receptors. These results indicate that IL-1 or TNF receptor signaling is not required for bacteria-induced osteoclastogenesis and bone loss, but does play a critical role in protecting the host against mixed anaerobic infections.

Interleukin-1 receptor signaling rather than that of tumor necrosis factor is critical in protecting the host from the severe consequences of a polymicrobe anaerobic infection.

ABSTRACT Infection of the dental pulp leads to an osteolytic lesion that results from a polymicrobial infection consisting largely of pathogenic anaerobes. Infection causes significant morbidity and mortality mediated by bacterial factors and in some cases by the up-regulation of inflammatory cytokines. The inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF), in particular, play a complex and central role in the responses to microbial pathogens. However, relatively little is known about the significance of these cytokines in protecting the host from focal polymicrobial anaerobic infections. To establish the relative importance of IL-1 and TNF in mediating the response to a mixed anaerobic infection, we inoculated the dental pulp of mice with six anaerobic pathogens containing functional deletions of receptors to IL-1 (IL-1R1−/−), TNF (TNFRp55−/−-p75−/−), or both (TNFRp55−/−-IL-1RI−/−). The results indicate that IL-1 receptor signaling and TNF receptor signaling both play similarly important roles in protecting the host from local tissue damage. However, IL-1 receptor signaling is considerably more important than TNF receptor signaling in preventing the spread of infection into surrounding fascial planes, since IL-1R1−/− but not TNFRp55−/−-p75−/− mice exhibited significantly higher morbidity and mortality. Moreover, all of the fatal infections occurred in male mice, suggesting the importance of gender differences in limiting the impact of these infections.

Endodontic pathogens stimulate monocyte chemoattractant protein-1 and interleukin-8 in mononuclear cells

Microbial infection of the dental pulp leads to the recruitment of leukocytes and the formation of lesions of endodontic origin. The chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) are relatively specific chemoattractants for neutrophils and monocytes, respectively. In the present studies, peripheral blood mononuclear cells were stimulated by Streptococcus mutants, Porphyromonas endodontalis, and Peptostreptococcus anaerobius, which are associated with lesions of endodontic origin. Each of these bacteria induced a dose-dependent increase in IL-8 and MCP-1, determined by ELISA. The levels induced are physiologically relevant. However, low doses of P. endodontalis were less effective in inducing IL-8 or MCP-1 expression, compared with S. mutants or P. anaerobius. Thus, these bacteria can induce significant levels of the chemokines IL-8 and MCP-1, which could contribute to the recruitment of neutrophils or monocytes in vivo. The expression of these mediators may contribute to the development of endodontic infections, particularly with regard to inflammatory leukocyte recruitment.

Leukocyte adhesion molecules.

Recruitment of leukocytes is critical to many of the processes studied in oral biology. With the development of new tools such as monoclonal antibody production and transgenic mice, the specific adhesion molecules thought to be important in leukocyte recruitment have been identified and their function examined. These molecules can be divided into three major classes: selectins, members of the immunoglobulin superfamily, and integrins. They mediate interactions between leukocytes and endothelial cells, facilitating the initial process of leukocyte rolling, firm attachment to endothelium, transendothelial migration, diapedesis, and migration along connective tissue. The goal of this paper is to provide an understanding of which molecules are involved in the above processes by discussing their cellular distribution, counter-receptors, and physiologic function.

An Optimal Host Response to a Bacterium May Require the Interaction of Leukocytes and Resident Host Cells

Bacterial infection results in inflammatory responses that may lead to soft-tissue damage and bone resorption. However, the mechanisms by which different bacteria contribute to lesions of endodontic origin are not fully understood. This study examined the response to Streptococcus mutans and Porphyromonas endodontalis in two cell types that are involved in periapical pathology, mononuclear and osteoblastic cells. This was accomplished by measuring the induction of chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-2) and proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, interleukin-6, interferon-gamma). The results demonstrated that S. mutans more efficiently stimulate inflammatory cytokine production by mononuclear cells, whereas P. endodontalis is relatively more potent in activating osteoblastic cells. Moreover, optimal activation of osteoblastic cells by S. mutans requires soluble mediators produced by mononuclear cells, whereas P. endodontalis does not. These results suggest that the association of different bacteria with specific pathologic processes may be partially explained by their capacities to activate specific host cells.