Defining the role of IL-1 and TNF in the pathogenesis of lesions of endodontic origin using genetically engineered mice
Date
1998
DOI
Authors
Chen, Chih-Ping
Version
OA Version
Citation
Abstract
Lesions of endodontic origin (LEOs) develop as a result of an immunopathological response to bacteria residing in infected root canal systems of an affected tooth. Convincing evidence has accumulated that a lesion of endodontic origin is a polymicrobial infection with anaerobes being the most frequently found pathogens. Bacterial infection of the dental pulp results first in pulpal destruction, and ultimately in the development of a periradicular inflammatory reaction with the concomitant resorption of the surrounding bone. Recently, bone resorptive cytokines (IL-1, TNF, IL-6) and other mediators (bradykinin, prostaglandins, leukotrienes) have been identified in pulp and periradicular tissue following endodontic infection. These mediators are absent or present in very low levels in normal tissue. Hence, the host immune response, in addition to bacterial factors, is assumed to be involved in the pathogenesis of lesions of endodontic origin.
IL-1 and TNF are a complex group of proteins able to exert pleiotropic effects with respect to a number of different target cells. IL-1 and TNF share several biologic activities and apparently play a similar role in many pathophysiologic reactions. With few exceptions, IL-1 and TNF act synergistically in both in vivo and in vitro studies. The implementation of such a variety of effects by a single cytokine is achieved by complex patterns of cell-specific gene regulation. Moreover, because of the functional redundancy of the cytokine family, it has been difficult to precisely assess the role of a single cytokine in the process of inflammation and host resistance to infectious agents. The generation and availability of mice lacking cytokines or cytokine receptors through targeted gene mutation allows for a more exact determination of the role of a particular cytokine in physiological homeostasis and the pathogenesis of disease states.
IL-1 and TNF activity are significantly enhanced in lesions of endodontic origin. It is not known whether they play a protective or destructive role. To address this issue, we examined normal mice and three groups of genetically engineered mice with targeted deletions of the IL-1 and/or TNF receptors. These mice were incapable of responding to IL-1 (IL-1RI[-/-]), TNF (TNFp55[-/-]-p75[-/-]) or both (TNFp55[-/-]-IL-1R1[-/-]). The dental pulp was exposed and inoculated with six putative endodontic pathogens. After certain time intervals, ranging from 0 to 38 days, specimens were harvested and subjected to quantitative histomorphometric and bacterial analysis. In the TNFp55[-/-]-IL-1R1[-/-]) mice, total pulpal necrosis was observed within 3 days; similar levels of necrosis did not occur in normal mice until 38 days. Bacterial penetration to the root end was greatest in the TNFp55[-/-]-IL-1R1[-/-]) mice, intermediate in IL-1R1[-/-] or TNFp55[-/-]-p75[-/-], and considerably less in the normal mice (p[less than]0.01). The size of lesions of endodontic origin followed the same pattern; at day 38 the TNFp55[-/-]-IL-1R1[-/-] was larger than either the IL-1R1[-/-] or TNFp55[-/-]-p75[-/-] or normal mice. Osteoclast activity peaked at day 7 for the receptor-deficient mice compared to a peak at day 38 for normal mice. The inflammatory cells, including PMNs and monocytes , recruitment in lesions of endodontic origin are still present in mice which lack the response to IL-1 and/or TNF, although it is qualitatively and quantitatively different compared to normal mice. We conclude that IL-I and TNF play an essential and synergistic role in protecting the host from endodontic pathogens. An inability to respond to IL-1 or TNF greatly enhances bacterial penetration and tissue damage.
Description
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Dissertation (D.Sc.D.)--Boston University, Henry M. Goldman School of Dental Medicine, 1998 (Endotology).
Includes bibliographic references: leaves 50-72.
Dissertation (D.Sc.D.)--Boston University, Henry M. Goldman School of Dental Medicine, 1998 (Endotology).
Includes bibliographic references: leaves 50-72.
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This work is protected by copyright. Downloading is restricted to the BU community. If you are the author of this work and would like to make it publicly available, please contact open-help@bu.edu.