Defensins Attenuate Cytokine Responses Yet Enhance Antibody Responses to
            <i>Porphyromonas Gingivalis</i>
            Adhesins in Mice

Kohlgraf, Karl G.; Ackermann, Abbey; Lü, Xiaoying; Burnell, Kindra K.; Bélanger, Myriam; Cavanaugh, Joseph E.; Xie, Hua; Progulske‐Fox, Ann; Brogden, Kim A.

doi:10.2217/fmb.09.107

Cited by 30 publications

(23 citation statements)

References 38 publications

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“…HNP-1 has been shown to block the ATP-induced IL-1β release from lipopolysaccharide (LPS)-activated human monocytes (31). In another study, HNP-1 and HNP-2 attenuated IL-6 and keratinocyte-derived chemokine responses to recombinant hemagglutinin B from Porphyromonas gingivalis (rHagB) (32). HNP-1-3 reduced the production of several pro-inflammatory cytokines, including TNF-α, from LPS- or CD40L/interferon-γ-stimulated human monocyte-derived macrophages.…”

Section: Discussionmentioning

confidence: 99%

Low concentrations of human neutrophil peptide ameliorate experimental murine colitis

Maeda

Sakiyama

Kanmura

et al. 2016

International Journal of Molecular Medicine

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Human neutrophil peptides (HNPs) not only have antimicrobial properties, but also exert multiple immunomodulatory effects depending on the concentration used. We have previously demonstrated that the intraperitoneal administration of high-dose HNP-1 (100 µg/day) aggravates murine dextran sulfate sodium (DSS)-induced colitis, suggesting a potential pro-inflammatory role for HNPs at high concentrations. However, the role of low physiological concentrations of HNPs in the intestinal tract remains largely unknown. The aim of this study was to examine the effects of low concentrations of HNPs on intestinal inflammation. We first examined the effects of the mild transgenic overexpression of HNP-1 in DSS-induced colitis. HNP-1 transgenic mice have plasma HNP-1 levels similar to the physiological concentrations in human plasma. Compared to wild-type mice treated with DSS, HNP-1 transgenic mice treated with DSS had significantly lower clinical and histological scores, and lower colonic mRNA levels of pro-inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α. We then injected low-dose HNP-1 (5 µg/day) or phosphate-buffered saline (PBS) intraperitoneally into C57BL/6N and BALB/c mice administered DSS. The HNP-1-treated mice exhibited significantly milder colitis with reduced expression levels of pro-inflammatory cytokines compared with the PBS-treated mice. Finally, we examined the in vitro effects of HNP-1 on the expression of cytokines associated with macrophage activation. Low physiological concentrations of HNP-1 did not significantly affect the expression levels of IL-1β, TNF-α, IL-6 or IL-10 in colonic lamina propria mononuclear cells activated with heat-killed Escherichia coli, suggesting that the anti-inflammatory effects of HNP-1 on murine colitis may not be exerted by direct action on intestinal macrophages. Collectively, our data demonstrated a biphasic dose-dependent effect of HNP-1 on DSS-induced colitis: an amelioration at low concentrations and an aggravation at high concentrations. Low concentrations of HNPs may contribute to the maintenance of intestinal homeostasis.

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Section: Discussionmentioning

confidence: 99%

Low concentrations of human neutrophil peptide ameliorate experimental murine colitis

Maeda

Sakiyama

Kanmura

et al. 2016

International Journal of Molecular Medicine

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“…Meanwhile, several recent reports have shown that low levels of HNP 1 could suppress the release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α [21][22][23] and increase IL-10 mRNA expression in the intestinal tissue [18] . These results demonstrate that HNPs have immunomodulatory effects that are concentration dependent.…”

Section: Discussionmentioning

confidence: 99%

Fecal Human Neutrophil Peptide Levels Correlate with Intestinal Inflammation in Ulcerative Colitis

et al. 2016

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Background/Aim: Fecal markers have recently been found to provide convenient and noninvasive assessment of intestinal inflammation in inflammatory bowel disease (IBD). In this study, we examined the clinical significance of fecal human neutrophil peptides (F-HNP) in the evaluation of IBD disease activity. Methods: This study enrolled 70 patients with IBD, consisting of 45 patients with ulcerative colitis (UC), 25 patients with Crohn's disease (CD), and 11 non-IBD controls. Stools samples were evaluated for the association between F-HNP concentration and disease and endoscopic activity in each group and the correlation between F-HNP and fecal calprotectin (F-CP) concentrations. Results: Median F-HNP levels were as follows: UC: 25.6 ng/ml; CD: 20.1 ng/ml; and non-IBD controls: 4.9 ng/ml. F-HNP levels were significantly higher in each IBD group, especially in the UC group, than in the control group. In the UC group, both F-HNP and F-CP levels were significantly higher during active disease compared to the remission phase. Both markers were significantly correlated with the Mayo endoscopic score, although the correlation was stronger for F-HNP than for F-CP (r = 0.66 vs. r = 0.54). Conclusion: F-HNP is a noninvasive marker that is useful for evaluating UC endoscopic activity.

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“…Previous studies suggest that further prophylactic and therapeutic approaches against periodontal diseases associated with P. gingivalis could be developed based on hemagglutinins. For example, human alpha- and beta- defensins were shown to bind P. gingivalis rHagB and enhance the IgG response in mice which could potentially lead to P. gingivalis clearance from the host [58–59]. HagA has been recognized by serum from a periodontal patient while we have previously reported that HagA expression in a S. enterica serovar Enterica vaccine strain was able to induce a humoral immune response against this hemagglutinin [40].…”

Section: Discussionmentioning

confidence: 99%

Both the unique and repeat regions of the Porphyromonas gingivalis hemagglutin A are involved in adhesion and invasion of host cells

et al. 2012

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Porphyromonas gingivalis is one of the major etiologic agents of adult periodontitis and has been associated with cardiovascular diseases. It expresses multiple hemagglutinins that are significant virulence factors that play an important role in bacterial attachment and invasion of host cells. The objective of this study was to determine the impact of P. gingivalis hemagglutinin A (HagA) on the attachment to and invasion of human coronary artery endothelial cells (HCAEC) and gingival epithelial cells (GEC). Bacterial strains expressing the HagA protein (or subunits), including Escherichia coli carrying plasmid pEKS5, E. coli carrying plasmid ST2, and Salmonella enterica serovar Typhimurium with plasmid pNM1.1 were used in this study. The strains were tested for their ability to attach to and invade HCAEC and GEC using antibiotic protection assays. In addition, the unique 5′ N-terminal non-repeated segment of HagA was purified in recombinant form and a monoclonal antibody was created against the polypeptide. The monoclonal antibody against the unique portion of HagA was tested for inhibitory activity in these assays. The attachment of both E. coli strains expressing HagA fragment to host cells was significantly increased compared to their respective controls. However they did not invade GEC or HCAEC. Interestingly, HagA expression in the Salmonella strain increased both adherence to and invasion of HCAEC, which may be due to the presence of the entire hagA ORF. A monoclonal antibody against the unique 5′ N-terminal portion of HagA reduced invasion. Further experiments are needed to determine the role of the unique and the repeat segments of P. gingivalis HagA.

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Defensins Attenuate Cytokine Responses Yet Enhance Antibody Responses to Porphyromonas Gingivalis Adhesins in Mice

Cited by 30 publications

References 38 publications

Low concentrations of human neutrophil peptide ameliorate experimental murine colitis

Low concentrations of human neutrophil peptide ameliorate experimental murine colitis

Fecal Human Neutrophil Peptide Levels Correlate with Intestinal Inflammation in Ulcerative Colitis

Both the unique and repeat regions of the Porphyromonas gingivalis hemagglutin A are involved in adhesion and invasion of host cells

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