Hu L, Bray MD, Osorio M, Kopecko DJ. Campylobacter jejuni induces maturation and cytokine production in human dendritic cells

Laboratory of Enteric and Sexually Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, NIH Campus, Bethesda, MD 20892, USA.
Infection and Immunity (Impact Factor: 3.73). 06/2006; 74(5):2697-705. DOI: 10.1128/IAI.74.5.2697-2705.2006
Source: PubMed


Campylobacter jejuni is a leading bacterial cause of human diarrheal disease in both developed and developing nations. Colonic mucosal invasion and the resulting host inflammatory responses are thought to be the key contributing factors to the dysenteric form of this disease. Dendritic cells (DCs) play an important role in both the innate and adaptive immune responses to microbial infection. In this study, the interaction between human monocyte-derived dendritic cells and C. jejuni was studied. We found that C. jejuni was readily internalized by DCs over a 2-h period. However, after a prolonged infection period (24 or 48 h) with C. jejuni, only a few viable bacteria remained intracellularly. Minimal cytotoxicity of C. jejuni to dendritic cells was observed. C. jejuni induced the maturation of dendritic cells over 24 h, as indicated by up-regulation of cell surface marker proteins CD40, CD80, and CD86. In addition, Campylobacter-infected DCs triggered activation of NF-kappaB and significantly stimulated production of interleukin-1beta (IL-1beta), IL-6, IL-8, IL-10, IL-12, gamma interferon, and tumor necrosis factor alpha (TNF-alpha) compared to uninfected DCs. Active bacterial invasion of DCs was not necessary for the induction of these cytokines, as heat-killed C. jejuni stimulated similar levels of cytokine production as live bacteria. Purified lipooligosaccharide of C. jejuni appears to be the major stimulant for the increased production of cytokines by DCs. Taken together, these data indicate that during infection, Campylobacter triggers an innate inflammatory response through increased production of IL-1beta, IL-6, IL-8, and TNF-alpha and initiates a Th1-polarized adaptive immune response as predicted from the high level of production of IL-12.

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Available from: Lan Hu, Jul 17, 2014
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    • "Infection of mice followed by systemic C. jejuni spread and the infection of internal organs has indicated that the mouse is a useful in vivo model to demonstrate bacterial dissemination and tissue invasion (Vu ckovicét al., 1998). A significant part of C. jejuni pathogenesis is connected with the effects of lipopolysaccharides, which are responsible for the production of several cytokines (Hu et al., 2006). "
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    ABSTRACT: Abstract Campylobacters have developed a number of mechanisms for responding to environmental conditions, although the different virulence properties of these cells following exposure to stress are still poorly understood. We analyzed in vitro stress responses and the consequent in vivo modulation of Campylobacter jejuni pathogenicity in BALB/c mice, as a result of the exposure of the C. jejuni to environmental stress (starvation, oxidative stress, heat shock). In vitro, the influence of starvation and oxidative stress was milder than that of heat shock, although the majority of the stress conditions influenced the survival of C. jejuni. During starvation, C. jejuni viability was maintained longer than its culturability. Additionally, starvation elicited transformation of stressed bacteria to coccoid forms. In contrast, bacteria exposed to oxygen remained culturable, but their viability decreased. Pre-starvation did not contribute to improved survival of C. jejuni cells during oxygen exposure. Changes in bacteria numbers and the levels of several cytokines (interleukins 6 and 10, tumor necrosis factor-α, interferon-γ) were followed in vivo, in liver homogenates from the mice intravenously infected with either control (untreated) or stressed C. jejuni. The systemic infection with the control or stressed C. jejuni occurred with different production dynamics of the cytokines investigated. Starvation was the most powerful stress factor, which significantly decreased infectious potential of C. jejuni during the first 3 days postinfection. The most pronounced differences in cytokine production were found in interferon-γ and interleukin-10 production, which indicates that these have roles in the immune response to C. jejuni infection. These in vivo studies of environmental impact on bacterial virulence reveal that microbial adaptation during stress challenge is crucial not just for pathogen survival out of the host, but also during host-pathogen interactions, and thus for the bacterial pathogenicity.
    Foodborne Pathogens and Disease 05/2013; 10(6). DOI:10.1089/fpd.2012.1298 · 1.91 Impact Factor
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    • "C. jejuni invades epithelial cells in vitro [3], and can be isolated from the spleen and liver in infected animals [4,5]. In vitro studies demonstrated the production of proinflammatory cytokines in C. jejuni-infected monocytic [6], dendritic [7] and intestinal epithelial cell lines [8], peripheral blood mononuclear cells [9] and splenocytes [10]. The association between cytokine production and disease protection/resolution, suggested in patients [9], was shown by the increased susceptibility of mice deficient in MyD88 or NF-κB to C. jejuni[11,12]. "
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    ABSTRACT: Background Cytokine production and histopathological changes occur in the lungs of mice after intranasal inoculation with Campylobacter jejuni, but the levels of cytokines in different organs to which C. jejuni disseminates have not been studied. Findings Adult BALB/c mice were intranasally inoculated with C. jejuni 81–176 (test) or phosphate-buffered saline (control) (n=16 per group). The levels of cytokines in the organs (spleen, liver, and small and large intestines) to which C. jejuni disseminated were measured by ELISA. Two cytokine patterns were observed. First, increased proinflammatory cytokines, TNF-α, IL-1, and IL-2, were followed by anti-inflammatory cytokines, IL-4 and IL-10 in the spleen and large intestine. Second, in the liver and small intestine, there was a predominant production of anti-inflammatory cytokines, IL-4 and IL-10, with some increase in IL-2 levels. In the spleen and intestines, the levels of pro- and anti-inflammatory cytokines were concurrently increased. Conclusion Dissemination of C. jejuni is associated with the production of different cytokine profiles in different tissues, with the proinflammatory response appearing in the spleen and large intestine at an earlier time point than in the liver and small intestine. The organs produce different cytokine profiles in response to C. jejuni dissemination. These preliminary findings should be confirmed with a study involving a larger group of animals.
    Gut Pathogens 12/2012; 4(1):23. DOI:10.1186/1757-4749-4-23 · 2.28 Impact Factor
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    • "Dendritic cells (DC) are critical sentinel cells that relay microbial presence either directly or indirectly (the latter via signals received from the overlaying epithelial lining of the gut) to naïve T cells; thus instructing the adaptive immune system to mount an appropriate response, which in a healthy host should promote successful bacterial clearance while registering memory [11]. Several studies have previously documented C. jejuni-mediated effects on murine [12] and human [13], [14] DC however, the impact of bacterial-DC cross-talk on human T cell immunity remains less clear. Here, we show that supernatants from C. jejuni-infected DC promoted significant expansion of Th-17, Th-1 and Th-17/Th-1 double-positive T cells. "
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    ABSTRACT: Campylobacter jejuni is the most prevalent cause of bacterial gastroenteritis worldwide. Despite the significant health burden this infection presents, molecular understanding of C. jejuni-mediated disease pathogenesis remains poorly defined. Here, we report the characterisation of the early, innate immune response to C. jejuni using an ex-vivo human gut model of infection. Secondly, impact of bacterial-driven dendritic cell activation on T-cell mediated immunity was also sought. Healthy, control paediatric terminal ileum or colonic biopsy tissue was infected with C. jejuni for 8-12 hours. Bacterial colonisation was followed by confocal microscopy and mucosal innate immune responses measured by ELISA. Marked induction of IFNγ with modest increase in IL-22 and IL-17A was noted. Increased mucosal IL-12, IL-23, IL-1β and IL-6 were indicative of a cytokine milieu that may modulate subsequent T-cell mediated immunity. C. jejuni-driven human monocyte-derived dendritic cell activation was followed by analyses of T cell immune responses utilising flow cytometry and ELISA. Significant increase in Th-17, Th-1 and Th-17/Th-1 double-positive cells and corresponding cytokines was observed. The ability of IFNγ, IL-22 and IL-17 cytokines to exert host defence via modulation of C. jejuni adhesion and invasion to intestinal epithelia was measured by standard gentamicin protection assay. Both innate and adaptive T cell-immunity to C. jejuni infection led to the release of IFNγ, IL-22 and IL-17A; suggesting a critical role for this cytokine triad in establishing host anti-microbial immunity during the acute and effectors phase of infection. In addition, to their known anti-microbial functions; IL-17A and IL-17F reduced the number of intracellular C. jejuni in intestinal epithelia, highlighting a novel aspect of how IL-17 family members may contribute to protective immunity against C. jejuni.
    PLoS ONE 11/2010; 5(11):e15398. DOI:10.1371/journal.pone.0015398 · 3.23 Impact Factor
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