Abstract
Chronic periodontitis (CP) is an infectious inflammatory disease that affects tooth-supporting structures and in which dental plaque bacteria, immune mechanisms and genetic predisposition play important roles. Interleukin 4 (IL-4) is a key anti-inflammatory cytokine with relevant action in imbalances in inflamed periodontal tissue. Individuals carrying the TCI/CCI genotype (S-haplotype) of the IL-4 gene are 5 times more susceptible to CP, whereas the CTI/TTD genotype (P-haplotype) confers protection against CP. Compared with the S-haplotype, subjects with the P-haplotype produce higher levels of the IL-4 protein after non-surgical periodontal therapy. The present in vitro study aimed to investigate the functionality of IL-4 haplotypes in immune cells to obtain insight into the influence of these genetic variations in regulating immune responses to CP-associated bacteria. Peripheral blood was collected from 6 subjects carrying each haplotype, and their immune cells were challenged with periodontopathogens to compare responses of the different haplotypes with regard to gene expression, protein secretion and the immunophenotype of T helper responses. We found higher IL-4 mRNA and protein levels in the P-haplotype, which also presented higher levels of anti-inflammatory cytokines. In contrast, cells from S-haplotype subjects responded with higher levels of pro-inflammatory cytokines. S-haplotype individuals exhibited significantly greater polarization toward the Th1 phenotype, whereas the P-haplotype was associated with an attenuated response to periodontopathogens, with suggestive skewing toward Th2/M2 phenotypes. In conclusion, IL-4 genetic variations associated with susceptibility to or protection against chronic periodontitis are directly associated with influencing the response of immune cells to periodontopathogens.
Highlights
Chronic periodontitis (CP) is an inflammatory disease that results from interaction between dental biofilm agents and the host immune response [1]
In support of this rationale, differences in levels of interleukins are attributed to polymorphisms in the corresponding genes [10], and genetic susceptibility to periodontal disease has been demonstrated to be associated with variations in genes with functional relevance to the immune response [11, 12]
Influence of Interleukin 4 (IL-4) haplotypes on cytokine gene expression by different immune cells
Summary
Chronic periodontitis (CP) is an inflammatory disease that results from interaction between dental biofilm agents and the host immune response [1]. Periodontopathogens, such as Porphyromonas gingivalis (Pg), Tannerella forsythia, Treponema denticola and Aggregatibacter actinomycetemcomitans (Aa), are abundant in subgingival biofilms at periodontitis-affected sites [2] and trigger an innate host response through Toll-like receptors (TLRs) expressed by resident cells and leukocytes in the periodontal microenvironment [3]. In support of this rationale, differences in levels of interleukins are attributed to polymorphisms in the corresponding genes [10], and genetic susceptibility to periodontal disease has been demonstrated to be associated with variations in genes with functional relevance to the immune response [11, 12]
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