Genetically Detoxified Pertussis Toxin Induces Th1/Th17 Immune Response through MAPKs and IL-10-Dependent Mechanisms

Nasso, Maria; Fedele, Giorgio; Spensieri, Fabiana; Palazzo, Raffaella; Costantino, Paolo; Rappuoli, Rino; Ausiello, Clara Maria

doi:10.4049/jimmunol.0901071

Cited by 55 publications

(67 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Indeed, the release of IL-12 was also shown to be upregulated in IL-32g-stimulated DCs. The simultaneous stimulation of Th1 and Th17 type responses has also been described previously by other investigators (35)(36)(37). Both the Th1 and Th17 subsets promote cellular immune function and can induce inflammation and autoimmune diseases, such as inflammatory bowel diseases and collagen-induced arthritis (17, 20, 38, 39).…”

Section: Discussionsupporting

confidence: 57%

IL-32γ Induces the Maturation of Dendritic Cells with Th1- and Th17-Polarizing Ability through Enhanced IL-12 and IL-6 Production

Jung

Son

Kim

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

IL-32, a newly described multifunctional cytokine, has been associated with a variety of inflammatory diseases, including rheumatoid arthritis, vasculitis, and Crohn’s disease. In this study, we investigated the immunomodulatory effects of IL-32γ on bone marrow-derived dendritic cell (DC)-driven Th responses and analyzed the underlying signaling events. IL-32γ–treated DCs exhibited upregulated expression of cell-surface molecules and proinflammatory cytokines associated with DC maturation and activation. In particular, IL-32γ treatment significantly increased production of IL-12 and IL-6 in DCs, which are known as Th1- and Th17-polarizing cytokines, respectively. This increased production was inhibited by the addition of specific inhibitors of the activities of phospholipase C (PLC), JNK, and NF-κB. IL-32γ treatment increased the phosphorylation of JNK and the degradation of both IκBα and IκBβ in DCs, as well as NF-κB binding activity to the κB site. The PLC inhibitor suppressed NF-κB DNA binding activity and JNK phosphorylation increased by IL-32γ treatment, thereby indicating that IL-32γ induced IL-12 and IL-6 production in DCs via a PLC/JNK/NF-κB signaling pathway. Importantly, IL-32γ–stimulated DCs significantly induced both Th1 and Th17 responses when cocultured with CD4+ T cells. The addition of a neutralizing anti–IL-12 mAb abolished the secretion of IFN-γ in a dose-dependent manner; additionally, the blockage of IL-1β and IL-6, but not of IL-21 or IL-23p19, profoundly inhibited IL-32γ–induced IL-17 production. These results demonstrated that IL-32γ could effectively induce the maturation and activation of immature DCs, leading to enhanced Th1 and Th17 responses as the result of increased IL-12 and IL-6 production in DCs.

show abstract

Section: Discussionsupporting

confidence: 57%

IL-32γ Induces the Maturation of Dendritic Cells with Th1- and Th17-Polarizing Ability through Enhanced IL-12 and IL-6 Production

Jung

Son

Kim

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…We have recently shown that MDDCs stimulated with genetically detoxified PT induced a mixed Th1/ Th17 response (15), and in another study PT-deficient B. pertussis was described as a poor inducer of both IFN-g and IL-17 in mice (17). The findings presented here demonstrate that detoxification of PT in BPZE1 results in two interesting properties: it abrogates toxicity and the inhibitory effects on chemotaxis while the immunomodulatory properties are retained.…”

Section: Discussionsupporting

confidence: 54%

“…In particular, our studies shed light on the contribution of several virulence factors, such as adenylate cyclase toxin (9-11), lipooligosaccharide (12,13), and PT (14,15).…”

mentioning

confidence: 96%

Attenuated Bordetella pertussis Vaccine Candidate BPZE1 Promotes Human Dendritic Cell CCL21-Induced Migration and Drives a Th1/Th17 Response

Fedele

Bianco

Debrie

et al. 2011

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

New vaccines against pertussis are needed to evoke full protection and long-lasting immunological memory starting from the first administration in neonates—the major target of the life-threatening pertussis infection. A novel live attenuated Bordetella pertussis vaccine strain, BPZE1, has been developed by eliminating or detoxifying three important B. pertussis virulence factors: pertussis toxin, dermonecrotic toxin, and tracheal cytotoxin. We used a human preclinical ex vivo model based on monocyte-derived dendritic cells (MDDCs) to evaluate BPZE1 immunogenicity. We studied the effects of BPZE1 on MDDC functions, focusing on the impact of Bordetella-primed dendritic cells in the regulation of Th and suppressor T cells (Ts). BPZE1 is able to activate human MDDCs and to promote the production of a broad spectrum of proinflammatory and regulatory cytokines. Moreover, conversely to its parental wild-type counterpart BPSM, BPZE1-primed MDDCs very efficiently migrate in vitro in response to the lymphatic chemokine CCL21, due to the inactivation of pertussis toxin enzymatic activity. BPZE1-primed MDDCs drove a mixed Th1/Th17 polarization and also induced functional Ts. Experiments performed in a Transwell system showed that cell contact rather than the production of soluble factors was required for suppression activity. Overall, our findings support the potential of BPZE1 as a novel live attenuated pertussis vaccine, as BPZE1-challenged dendritic cells might migrate from the site of infection to the lymph nodes, prime Th cells, mount an adaptive immune response, and orchestrate Th1/Th17 and Ts responses.

show abstract

“…Although many cell surface sialoglycoproteins may serve as PTX receptors, specific receptors for PTX have not been identified [13]. PTX induces intracellular signals in part through TLR4, and JNK, p38, ERK1/2, and NF-κB are all activated in response to PTX, similar to the response to LPS [6,14]. LPS signals through TLR4 via two major pathway types: the MyD88-dependent activation of NF-κB, which results in the induction of inflammatory genes, such as TNF, IL-6, and IL-1β, and TRIF-dependent pathways, which involve the induction of type I IFNs and secondary response genes that are activated by IFN-β in an autocrine/paracrine manner [15,16].…”

Section: Introductionmentioning

confidence: 99%

Differential IL‐10 production by DCs determines the distinct adjuvant effects of LPS and PTX in EAE induction

et al. 2014

View full text Add to dashboard Cite

Pertussis toxin (PTX) is used as an adjuvant to induce EAE in mice as a model of MS. Although LPS and PTX are similar in their ability to mature dendritic cells (DCs) and in their adjuvant properties, here we demonstrate that LPS does not induce EAE development. We also demonstrate that DCs treated with PTX (PTX-DCs) are able to induce EAE, whereas DCs treated with LPS (LPS-DCs) fail to induce EAE. We determine that a key difference between LPS-DCs and PTX-DCs is that LPS-DCs produce larger amounts of IL-10. IL-10−/− -DCs treated with LPS promote stronger IFN-γ and IL-17 production and T-cell proliferation than WT DCs treated with LPS in a coculture system. Finally, we demonstrate that EAE can be successfully induced when IL-10 −/− -DCs treated with LPS are used as an adjuvant, whereas the use of PTX-DCs overexpressing IL-10 as an adjuvant markedly controls EAE development. These results indicate that the inability of LPS to induce EAE is based on the induction of high levels of IL-10 in the targeted DCs, providing insight into the mechanisms responsible for the induction of EAE.Keywords: Dendritic cells r EAE r IL-10 r LPS r Pertussis toxin (PTX)Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMS is a chronic autoimmune disease of the CNS. MS is characterized by inflammation, demyelination, and axonal pathology and is thought to occur in genetically predisposed individuals following exposure to an environmental trigger that activates myelin-specific pathogenic T cells that can cross the blood-brain barrier. EAE is Correspondence: Prof. Bing Sun e-mail: bsun@sibs.ac.cn; Yong-Jun.Liu@BaylorHealth.edu a mouse model for studying MS. MS and EAE were previously thought to be mediated by Th1 cells; however, numerous recent studies have provided strong evidence that IL-17-producing T cells play a dominant role in the pathogenesis of EAE [1][2][3]. Pertussis toxin (PTX) is an exotoxin that is produced by Bordetella pertussis. PTX blocks chemokine receptors such as CXCR4 and CCR5. PTX treatment causes a decrease in CXCR4 * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 1352-1362 Cellular immune response 1353 surface expression, inhibits G protein associated signaling, and blocks stromal cell derived factor 1 alpha mediated chemotaxis by activating the TCR signaling network [4]. However, the detailed mechanism by which PTX blocks CCR5 is unclear, although receptor crosstalk between an unknown PTX receptor and chemokine receptors has been suggested [4]. PTX has been widely used as an adjuvant to induce Th1/Th17-mediated organ-specific autoimmune diseases in animal models, including experimental autoimmune uveitis (EAU) and EAE. PTX has profound effects on the immune system and is thought to induce EAE by facilitating the "opening" of the blood-brain barrier [5,6]. PTX is also an adjuvant that acts on dendritic cells (DCs) to induce DCs activation, IL-12 ...

show abstract

Genetically Detoxified Pertussis Toxin Induces Th1/Th17 Immune Response through MAPKs and IL-10-Dependent Mechanisms

Cited by 55 publications

References 55 publications

IL-32γ Induces the Maturation of Dendritic Cells with Th1- and Th17-Polarizing Ability through Enhanced IL-12 and IL-6 Production

IL-32γ Induces the Maturation of Dendritic Cells with Th1- and Th17-Polarizing Ability through Enhanced IL-12 and IL-6 Production

Attenuated Bordetella pertussis Vaccine Candidate BPZE1 Promotes Human Dendritic Cell CCL21-Induced Migration and Drives a Th1/Th17 Response

Differential IL‐10 production by DCs determines the distinct adjuvant effects of LPS and PTX in EAE induction

Contact Info

Product

Resources

About