Campylobacter jejuni Induces Maturation and Cytokine Production in Human Dendritic Cells

ABSTRACT 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-κB and significantly stimulated production of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-12, gamma interferon, and tumor necrosis factor alpha (TNF-α) 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-1β, IL-6, IL-8, and TNF-α and initiates a Th1-polarized adaptive immune response as predicted from the high level of production of IL-12.

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Haemophilus influenzae Porin Induces Toll-Like Receptor 2-Mediated Cytokine Production in Human Monocytes and Mouse Macrophages

Infection and Immunity ◽

10.1128/iai.72.2.1204-1209.2004 ◽

2004 ◽

Vol 72 (2) ◽

pp. 1204-1209 ◽

Cited By ~ 51

Author(s):

Marilena Galdiero ◽

Massimiliano Galdiero ◽

Emiliana Finamore ◽

Fabio Rossano ◽

Maria Gambuzza ◽

...

Keyword(s):

Haemophilus Influenzae ◽

Cytokine Production ◽

Inflammatory Responses ◽

Adaptor Protein ◽

Monocytic Cell ◽

Monocytic Cell Line ◽

Necrosis Factor Alpha ◽

Human Monocytic Cell Line ◽

Tnf Α ◽

Human Monocytic Cell

ABSTRACT The production of proinflammatory cytokines is likely to play a major pathophysiological role in meningitis and other infections caused by Haemophilus influenzae type b (Hib). Previous studies have shown that Hib porin contributes to signaling of the inflammatory cascade. We examined here the role of Toll-like receptors (TLRs) and the TLR-associated adaptor protein MyD88 in Hib porin-induced production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Hib porin-induced TNF-α and IL-6 production was virtually eliminated in macrophages from TLR2- or MyD88-deficient mice. In contrast, macrophages from lipopolysaccharide (LPS)-hyporesponsive C3H/HeJ mice, which are defective in TLR4 function, responded normally to Hib porin. Moreover anti-TLR2 antibodies but not anti-TLR4 antibodies significantly reduced Hib porin-stimulated TNF-α and IL-6 release from the human monocytic cell line THP-1. These data indicate that the TLR2/MyD88 pathway plays an essential role in Hib porin-mediated cytokine production. These findings may be useful in the development of alternative therapies aimed at reducing excessive inflammatory responses during Hib infections.

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Systemic Expression of Cytokine Production in Patients with Severe Pneumococcal Pneumonia: Effects of Treatment with a β-Lactam versus a Fluoroquinolone

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00658-07 ◽

2008 ◽

Vol 52 (7) ◽

pp. 2395-2402 ◽

Cited By ~ 22

Author(s):

Esther Calbo ◽

Montserrat Alsina ◽

Mónica Rodríguez-Carballeira ◽

Josep Lite ◽

Javier Garau

Keyword(s):

Pneumococcal Pneumonia ◽

Cytokine Production ◽

Inflammatory Responses ◽

Randomized Study ◽

Venous Blood ◽

Severe Pneumonia ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Severity Scores ◽

Over Time

ABSTRACT Bacterial alveolar invasion is followed by an inflammatory response. A systemic extension of the compartmentalized immune response has been described in patients with severe pneumonia. The data suggest that some antimicrobials may induce a differential release of cytokines. We conducted a prospective, randomized study in adult patients with severe pneumococcal pneumonia to measure the effects of ceftriaxone and levofloxacin in the systemic cytokine expression over time. Demographic, clinical characteristics, and severity scores were recorded. The serum concentrations of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8, IL-10, and IL-1 receptor agonist were measured at 0, 24, 72, and 120 h. A total of 32 patients were included in the study. Both groups were homogeneous in terms of age, comorbidities, severity of disease, and corticosteroid or statin use. With the single exception of IL-1β, all cytokines were detected in venous blood. All of the cytokines studied showed a similar pattern of progressive decrease over time. No significant differences in the concentrations of any of the cytokines studied were found, with the exception of TNF-α, for which lower concentrations were obtained at 120 h in the levofloxacin group (P = 0.014). Basal oxygen saturation (P = 0.034) and heart rate (P = 0.029) returned to normal values earlier in the levofloxacin arm. We demonstrated that in patients with severe pneumococcal pneumonia pro- and anti-inflammatory responses could be detected in venous blood, representing a systemic extension of the compartmentalized response. Treatment with a β-lactam agent or a fluoroquinolone has different effects on cytokine production and its systemic expression, impacting the clinical course of the disease.

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Campylobacter jejuni-Mediated Induction of CC and CXC Chemokines and Chemokine Receptors in Human Dendritic Cells

Infection and Immunity ◽

10.1128/iai.00129-12 ◽

2012 ◽

Vol 80 (8) ◽

pp. 2929-2939 ◽

Cited By ~ 11

Author(s):

Lan Hu ◽

Mechelle D. Bray ◽

Yansheng Geng ◽

Dennis J. Kopecko

Keyword(s):

Dendritic Cells ◽

Campylobacter Jejuni ◽

Chemokine Receptors ◽

Molecular Mechanisms ◽

Immune Cell ◽

Diarrheal Disease ◽

Inflammatory Responses ◽

Lymphoid Tissues ◽

Contributing Factors ◽

Content Type

ABSTRACTCampylobacter jejuniis a leading worldwide bacterial cause of human diarrheal disease. Although the specific molecular mechanisms ofC. jejunipathogenesis have not been characterized in detail, host inflammatory responses are thought to be major contributing factors to the resulting typical acute colitis. The intestinal mucosal chemokine response is particularly important in the initial stages of bacterium-induced gut inflammation. Chemokines attract blood phagocytes and lymphocytes to the site of infection and regulate immune cell maturation and the development of localized lymphoid tissues. The production of chemokines by dendritic cells (DCs) followingCampylobacterinfection has not yet been analyzed. In the current study, we infected human monocyte-derived DCs withC. jejunito examine the production of key proinflammatory chemokines and chemokine receptors. The chemokines, including CC families (macrophage inflammatory protein 1α [MIP-1α], MIP-1β, RANTES) and CXC families (growth-related oncogene α [GRO-α], IP-10, and monokine induced by gamma interferon [MIG]), were upregulated inCampylobacter-infected DCs. Chemokine receptors CCR6 and CCR7, with roles in DC trafficking, were also induced inCampylobacter-infected DCs. Further,Campylobacterinfection stimulated the phosphorylation of P38, P44/42, and stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) mitogen-activated protein kinases (MAPKs) in DCs. NF-κB activation was specifically involved in chemokine induction in DCs infected withC. jejuni. Additionally, STAT3 was significantly increased inCampylobacter-infected DCs compared to that in uninfected DCs. These results suggest that DCs play a significant role in the initiation and modulation of the inflammatory response by enlisting monocytes, neutrophils, and T lymphocytes during human intestinal infection withCampylobacter.

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Campylobacter jejuni-Induced Activation of Dendritic Cells Involves Cooperative Signaling through Toll-Like Receptor 4 (TLR4)-MyD88 and TLR4-TRIF Axes

Infection and Immunity ◽

10.1128/iai.01562-08 ◽

2009 ◽

Vol 77 (6) ◽

pp. 2499-2507 ◽

Cited By ~ 43

Author(s):

Vijay A. K. Rathinam ◽

Daniel M. Appledorn ◽

Kathleen A. Hoag ◽

Andrea Amalfitano ◽

Linda S. Mansfield

Keyword(s):

Dendritic Cells ◽

Campylobacter Jejuni ◽

Inflammatory Responses ◽

Interleukin 1 ◽

Toll Like Receptor ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Myeloid Differentiation Factor ◽

Cooperative Signaling

ABSTRACT Campylobacter jejuni is an important cause of human enteritis and has been linked to the development of autoimmune diseases. Recently we showed that infection of murine dendritic cells (DCs) with C. jejuni resulted in DC activation and induction of Campylobacter-specific Th1-effector responses. Toll-like receptor (TLR) signaling through myeloid differentiation factor 88 (MyD88) and/or Toll-interleukin 1 (IL-1) receptor domain-containing adaptor-inducing beta interferon (IFN-β) (TRIF) is critical in inducing immunity against pathogens. In this study, we investigated the role of TLR2, TLR4, MyD88, and TRIF signaling in C. jejuni-induced inflammatory activation of DCs. DC upregulation of major histocompatibility complex class II and costimulatory molecules after C. jejuni challenge was profoundly impaired by TLR2, TLR4, MyD88, and TRIF deficiencies. Similarly, C. jejuni-induced secretion of IL-12, IL-6, and tumor necrosis factor alpha was significantly inhibited in TLR2−/−, TLR4−/−, MyD88−/−, and TRIF−/− DCs compared to that in wild-type DCs; however, the magnitude of inhibition was greater in MyD88−/−, TRIF−/−, and TLR4−/− DCs than in TLR2−/− DCs. Furthermore, C. jejuni induced interferon regulatory factor 3 phosphorylation and IFN-β secretion by DCs in a TLR4-TRIF-dependent fashion, further demonstrating activation of this pathway by C. jejuni. Importantly, TLR2, TLR4, MyD88, and TRIF deficiencies all markedly impaired the Th1-priming ability of C. jejuni-infected DCs. Thus, our results show that cooperative signaling through the TLR4-MyD88 and TLR4-TRIF axes represents a novel mechanism mediating C. jejuni-induced inflammatory responses of DCs. To our knowledge, such a mechanism has not been demonstrated previously for an intact bacterium.

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Anti-β2 Glycoprotein I Antibodies Cause Inflammation and Recruit Dendritic Cells in Platelet Clearance

Thrombosis and Haemostasis ◽

10.1055/s-0037-1616059 ◽

2001 ◽

Vol 86 (11) ◽

pp. 1257-1263 ◽

Cited By ~ 6

Author(s):

Attilio Bondanza ◽

Angelo Manfredi ◽

Valérie Zimmermann ◽

Matteo Iannacone ◽

Angela Tincani ◽

...

Keyword(s):

Dendritic Cells ◽

Inflammatory Responses ◽

Glycoprotein I ◽

Activated Platelets ◽

Tnf Α ◽

Per Se ◽

Antigen Presenting ◽

Antiinflammatory Cytokine

SummaryScavenger phagocytes are mostly responsible for the in vivo clearance of activated or senescent platelets. In contrast to other particulate substrates, the phagocytosis of platelets does not incite pro-inflammatory responses in vivo. This study assessed the contribution of macrophages and dendritic cells (DCs) to the clearance of activated platelets. Furthermore, we verified whether antibodies against the β2 Glycoprotein I (β2GPI), which bind to activated platelets, influence the phenomenon. DCs did not per se internalise activated platelets. In contrast, macrophages efficiently phagocytosed platelets. In agreement with the uneventful nature of the clearance of platelets in vivo, phagocytosing macrophages did not release IL-1β, TNF-α or IL-10. β2GPI bound to activated platelets and was required for their recognition by anti-ββ2GPI antibodies. DCs internalised platelets opsonised by anti-ββ2GPI antibodies. The phagocytosis of opsonised platelets determined the release of TNF-α and IL-1β by DCs and macrophages. Phagocytosing macrophages, but not DCs, secreted the antiinflammatory cytokine IL-1β0. We conclude that anti-ββ2GPI antibodies cause inflammation during platelet clearance and shuttle platelet antigens to antigen presenting DCs.

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Differential Regulation of Inflammatory Cytokine Secretion by Human Dendritic Cells upon Chlamydia trachomatis Infection

Infection and Immunity ◽

10.1128/iai.72.12.7231-7239.2004 ◽

2004 ◽

Vol 72 (12) ◽

pp. 7231-7239 ◽

Cited By ~ 57

Author(s):

Ana Gervassi ◽

Mark R. Alderson ◽

Robert Suchland ◽

Jean François Maisonneuve ◽

Kenneth H. Grabstein ◽

...

Keyword(s):

Dendritic Cells ◽

Chlamydia Trachomatis ◽

Wide Spectrum ◽

Cytokine Secretion ◽

Host Cells ◽

Microbial Pathogens ◽

Potential Contribution ◽

Necrosis Factor Alpha ◽

Chlamydia Trachomatis Infection ◽

Tnf Α

ABSTRACT Chlamydia trachomatis is an obligate intracellular gram-negative bacterium responsible for a wide spectrum of diseases in humans. Both genital and ocular C. trachomatis infections are associated with tissue inflammation and pathology. Dendritic cells (DC) play an important role in both innate and adaptive immune responses to microbial pathogens and are a source of inflammatory cytokines. To determine the potential contribution of DC to the inflammatory process, human DC were infected with C. trachomatis serovar E or L2. Both C. trachomatis serovars were found to infect and replicate in DC. Upon infection, DC up-regulated the expression of costimulatory (B7-1) and cell adhesion (ICAM-1) molecules. Furthermore, chlamydial infection induced the secretion of interleukin-1β (IL-1β), IL-6, IL-8, IL-12p70, IL-18, and tumor necrosis factor alpha (TNF-α). The mechanisms involved in Chlamydia-induced IL-1β and IL-18 secretion differed from those of the other cytokines. Chlamydia-induced IL-1β and IL-18 secretion required infection with viable bacteria and was associated with the Chlamydia-induced activation of caspase-1 in infected host cells. In contrast, TNF-α and IL-6 secretion did not require that the Chlamydia be viable, suggesting that there are at least two mechanisms involved in the Chlamydia-induced cytokine secretion in DC. Interestingly, an antibody to Toll-like receptor 4 inhibited Chlamydia-induced IL-1β, IL-6, and TNF-α secretion. The data herein demonstrate that DC can be infected by human C. trachomatis serovars and that chlamydial components regulate the secretion of various cytokines in DC. Collectively, these data suggest that DC play a role in the inflammatory processes caused by chlamydial infections.

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CD4+ CD25+ Foxp3+ Regulatory T Cells, Dendritic Cells, and Circulating Cytokines in Uncomplicated Malaria: Do Different Parasite Species Elicit Similar Host Responses?

Infection and Immunity ◽

10.1128/iai.00578-10 ◽

2010 ◽

Vol 78 (11) ◽

pp. 4763-4772 ◽

Cited By ~ 55

Author(s):

Raquel M. Gonçalves ◽

Karina C. Salmazi ◽

Bianca A. N. Santos ◽

Melissa S. Bastos ◽

Sandra C. Rocha ◽

...

Keyword(s):

Dendritic Cells ◽

Parasite Species ◽

Inflammatory Responses ◽

Clinical Symptoms ◽

Clinical Manifestations ◽

Surface Expression ◽

Interleukin 10 ◽

Treg Cells ◽

Experimental Models ◽

Necrosis Factor Alpha

ABSTRACT Clearing blood-stage malaria parasites without inducing major host pathology requires a finely tuned balance between pro- and anti-inflammatory responses. The interplay between regulatory T (Treg) cells and dendritic cells (DCs) is one of the key determinants of this balance. Although experimental models have revealed various patterns of Treg cell expansion, DC maturation, and cytokine production according to the infecting malaria parasite species, no studies have compared all of these parameters in human infections with Plasmodium falciparum and P. vivax in the same setting of endemicity. Here we show that during uncomplicated acute malaria, both species induced a significant expansion of CD4+ CD25+ Foxp3+ Treg cells expressing the key immunomodulatory molecule CTLA-4 and a significant increase in the proportion of DCs that were plasmacytoid (CD123+), with a decrease in the myeloid/plasmacytoid DC ratio. These changes were proportional to parasite loads but correlated neither with the intensity of clinical symptoms nor with circulating cytokine levels. One-third of P. vivax-infected patients, but no P. falciparum-infected subjects, showed impaired maturation of circulating DCs, with low surface expression of CD86. Although vivax malaria patients overall had a less inflammatory cytokine response, with a higher interleukin-10 (IL-10)/tumor necrosis factor alpha (TNF-α) ratio, this finding did not translate to milder clinical manifestations than those of falciparum malaria patients. We discuss the potential implications of these findings for species-specific pathogenesis and long-lasting protective immunity to malaria.

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Morin Promotes the Production of Th2 Cytokine by Modulating Bone Marrow-Derived Dendritic Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x06004193 ◽

2006 ◽

Vol 34 (04) ◽

pp. 667-684 ◽

Cited By ~ 10

Author(s):

Chia-Yang Li ◽

Jau-Ling Suen ◽

Bor-Luen Chiang ◽

Pei-Dawn Lee Chao ◽

Shih-Hua Fang

Keyword(s):

Bone Marrow ◽

T Cells ◽

Dendritic Cells ◽

Interleukin 12 ◽

Th2 Response ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Th Differentiation ◽

Th1 And Th2 Responses

Our previous studies had reported that morin decreased the interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-α) production in lipopolysaccharide (LPS)-activated macrophages, suggesting that morin may promote helper T type 2 (Th2) response in vivo. Dendritic cells (DCs) are the most potent antigen presenting cells and known to play a major role in the differentiation of helper T type 1 (Th1) and Th2 responses. This study aimed to reveal whether morin is able to control the Th differentiation through modulating the maturation and functions of DCs. Bone marrow-derived dendritic cells (BM-DCs) were incubated with various concentrations of morin and their characteristics were studied. The results indicated that morin significantly affects the phenotype and cytokine expression of BM-DCs. Morin reduced the production of IL-12 and TNF-α in BM-DCs, in response to LPS stimulation. In addition, the proliferative response of stimulated alloreactive T cells was significantly decreased by morin in BM-DCs. Furthermore, allogeneic T cells secreted higher IL-4 and lower IFN-γ in response to morin in BM-DCs. In conclusion, these results suggested that morin favors Th2 cell differentiation through modulating the maturation and function of BM-DCs.

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Oral Mucosal Endotoxin Tolerance Induction in Chronic Periodontitis

Infection and Immunity ◽

10.1128/iai.73.2.687-694.2005 ◽

2005 ◽

Vol 73 (2) ◽

pp. 687-694 ◽

Cited By ~ 107

Author(s):

Manoj Muthukuru ◽

Ravi Jotwani ◽

Christopher W. Cutler

Keyword(s):

Immune Response ◽

Oral Mucosa ◽

Chronic Periodontitis ◽

Intracellular Signaling ◽

Inflammatory Responses ◽

Endotoxin Tolerance ◽

Necrosis Factor Alpha ◽

Initial Stimulus ◽

Tlr4 Mrna ◽

Tnf Α

ABSTRACT The oral mucosa is exposed to a high density and diversity of gram-positive and gram-negative bacteria, but very little is known about how immune homeostasis is maintained in this environment, particularly in the inflammatory disease chronic periodontitis (CP). The cells of the innate immune response recognize bacterial structures via the Toll-like receptors (TLR). This activates intracellular signaling and transcription of proteins essential for the induction of an adaptive immune response; however, if unregulated, it can lead to destructive inflammatory responses. Using single-immunoenzyme labeling, we show that the human oral mucosa (gingiva) is infiltrated by large numbers of TLR2+ and TLR4+ cells and that their numbers increase significantly in CP, relative to health (P < 0.05, Student's t test). We also show that the numbers of TLR2+ but not TLR4+ cells increase linearly with inflammation (r 2 = 0.33, P < 0.05). Double-immunofluorescence analysis confirms that TLR2 is coexpressed by monocytes (MC)/macrophages (mφ) in situ. Further analysis of gingival tissues by quantitative real-time PCR, however, indicates that despite a threefold increase in the expression of interleukin-1β (IL-1β) mRNA during CP, there is significant (30-fold) downregulation of TLR2 mRNA (P < 0.05, Student's t test). Also showing similar trends are the levels of TLR4 (ninefold reduction), TLR5 (twofold reduction), and MD-2 (sevenfold reduction) mRNA in CP patients compared to healthy persons, while the level of CD14 was unchanged. In vitro studies with human MC indicate that MC respond to an initial stimulus of lipopolysaccharide (LPS) from Porphyromonas gingivalis (PgLPS) or Escherichia coli (EcLPS) by upregulation of TLR2 and TLR4 mRNA and protein; moreover, IL-1β mRNA is induced and tumor necrosis factor alpha (TNF-α), IL-10, IL-6, and IL-8 proteins are secreted. However, restimulation of MC with either PgLPS or EcLPS downregulates TLR2 and TLR4 mRNA and protein and IL-1β mRNA and induces a ca. 10-fold reduction in TNF-α secretion, suggesting the induction of endotoxin tolerance by either LPS. Less susceptible to tolerance than TNF-α were IL-6, IL-10, and IL-8. These studies suggest that certain components of the innate oral mucosal immune response, most notably TLRs and inflammatory cytokines, may become tolerized during sustained exposure to bacterial structures such as LPS and that this may be one mechanism used in the oral mucosa to attempt to regulate local immune responses.

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Mycoplasma pneumoniae-Derived Lipopeptides Induce Acute Inflammatory Responses in the Lungs of Mice

Infection and Immunity ◽

10.1128/iai.00955-07 ◽

2007 ◽

Vol 76 (1) ◽

pp. 270-277 ◽

Cited By ~ 40

Author(s):

Takashi Shimizu ◽

Yutaka Kida ◽

Koichi Kuwano

Keyword(s):

Mycoplasma Pneumoniae ◽

Inflammatory Responses ◽

Lavage Fluid ◽

Peritoneal Macrophages ◽

Necrosis Factor Alpha ◽

Chemokine Production ◽

Cytokines And Chemokines ◽

Tnf Α ◽

Mouse Peritoneal Macrophages

ABSTRACT The pathogenesis of Mycoplasma pneumoniae infection is considered to be in part attributable to excessive immune responses. In this study, we investigated whether synthetic lipopeptides of subunit b of F0F1-type ATPase (F0F1-ATPase), NF-κB-activating lipoprotein 1 (N-ALP1), and N-ALP2 (named FAM20, sN-ALP1, and sN-ALP2, respectively) derived from M. pneumoniae induce cytokine and chemokine production and leukocyte infiltration in vivo. Intranasal administration of FAM20 and sN-ALP2 induced infiltration of leukocyte cells and production of chemokines and cytokines in bronchoalveolar lavage fluid, but sN-ALP1 failed to do so. The activity of FAM20 was notably higher than that of sN-ALP2. FAM20 and sN-ALP2 induced tumor necrosis factor alpha (TNF-α) through Toll-like receptor 2 in mouse peritoneal macrophages. Moreover, in the range of low concentrations of lipopeptides, FAM20 showed relatively high activity of inducing TNF-α in mouse peritoneal macrophages compared to synthetic lipopeptides such as MALP-2 and FSL-1, derived from Mycoplasma fermentans and Mycoplasma salivarium, respectively. These findings indicate that the F0F1-ATPase might be a key molecule in inducing cytokines and chemokines contributing to inflammatory responses during M. pneumoniae infection in vivo.

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