Collaborative Action of NF-κB and p38 MAPK Is Involved in CpG DNA-Induced IFN-α and Chemokine Production in Human Plasmacytoid Dendritic Cells

Osawa, Yusuke; Iho, Sumiko; Takauji, Rumiko; Takatsuka, Hisakazu; Yamamoto, Saburo; Takahashi, Takayuki; Horiguchi, Satomi; Urasaki, Yoshimasa; Matsuki, Taizo; Fujieda, Shigeharu

doi:10.4049/jimmunol.177.7.4841

Cited by 71 publications

(64 citation statements)

References 59 publications

(67 reference statements)

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“…The CD5 + CD81 + pDCs express substantially less IRF7 mRNA than CD5 − CD81 − pDCs, which might explain their diminished type I IFN production. In contrast, these pDCs express a higher level of IRF5, a signaling factor in pDCs that can induce transcription of proinflammatory cytokines, chemokines, and costimulatory molecules, as well as IFNα/β (43)(44)(45)(46). This finding may explain their more abundant production of IL-6 and elevated expression of CD40, CD80, and CD86.…”

Section: Discussionmentioning

confidence: 37%

A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

Zhang

Gregorio

Iwahori³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Plasmacytoid dendritic cells (pDCs) are known mainly for their secretion of type I IFN upon viral encounter. We describe a CD2 hi CD5 + CD81 + pDC subset, distinguished by prominent dendrites and a mature phenotype, in human blood, bone marrow, and tonsil, which can be generated from CD34 + progenitors. These CD2 hi CD5 + CD81 + cells express classical pDC markers, as well as the toll-like receptors that enable conventional pDCs to respond to viral infection. However, their gene expression profile is distinct, and they produce little or no type I IFN upon stimulation with CpG oligonucleotides, likely due to their diminished expression of IFN regulatory factor 7. A similar population of CD5 + CD81 + pDCs is present in mice and also does not produce type I IFN after CpG stimulation. In contrast to conventional CD5 − CD81 − pDCs, human CD5 + CD81 + pDCs are potent stimulators of B-cell activation and antibody production and strong inducers of T-cell proliferation and Treg formation. These findings reveal the presence of a discrete pDC population that does not produce type I IFN and yet mediates important immune functions previously attributed to all pDCs.P lasmacytoid dendritic cells (pDCs) are a distinct lineage of bone-marrow-derived cells that reside mainly in blood and lymphoid organs in the steady state, but can also be found in sites of infection, inflammation, and cancer (1). As one of the two principal lineages of dendritic cells, pDCs diverge from conventional DCs (cDCs) during maturation in the bone marrow and are recognized mainly for their rapid and massive production of type I IFN (IFNα/β) in response to viral infection (2). Although generally viewed as weak antigen-presenting cells by comparison with cDCs, pDCs interact with many types of cells, such as NK cells, cDCs, T cells, and B cells through their secretion of cytokines and chemokines in addition to type I IFN, as well as through their expression of various costimulatory molecules (3, 4). Thus, pDCs are capable of activating CD4 + helper and regulatory T cells and CD8 + cytotoxic T cells (5-16). They can also stimulate B-cell activation, differentiation into plasma cells, and antibody production through mechanisms that are not yet completely understood (17)(18)(19)(20)(21)(22).Whether the diverse functions of pDCs are mediated by the same cells responding to different environmental cues or by distinct preprogrammed subsets or lineages is not clear, although several reports suggest the existence of phenotypically distinct subpopulations of pDCs in mice (23-25) and humans (26-30). Surface expression of CD2 divides human pDCs into two distinct subsets. Whereas both CD2 lo and CD2 hi pDCs produce type I IFN, the CD2 hi subset secretes more IL12p40, triggers more T-cell proliferation (26), and is relatively resistant to apoptosis on the basis of higher BCL2 expression (28). Here we show that CD2 hi pDCs contain a unique subpopulation that expresses CD5 and CD81. Unlike CD2 hi CD5 − CD81 − pDCs, CD2 hi CD5 + CD81 + pDCs fail to produce type 1 IFN but ...

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Section: Discussionmentioning

confidence: 37%

A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

Zhang

Gregorio

Iwahori³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…We show that it is controlled by the p38 MAPK. Accordingly, the involvement of p38 MAPK in the production of IFN-␣ by pDC has been shown (31,38), suggesting that some pathways of IFN production are conserved through cell types. We also found that, in HMCL, the production of IFN-␣ was coupled to that of IL-6.…”

Section: Discussionmentioning

confidence: 99%

TLR3 Ligand Induces NF-κB Activation and Various Fates of Multiple Myeloma Cells Depending on IFN-α Production

Chiron

Pellat‐Deceunynck

Amiot

et al. 2009

The Journal of Immunology

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Multiple myeloma (MM) cells express TLR. It has been shown that TLR ligands induce the proliferation, survival, and immune surveillance escape of MM cells through MyD88-TLR pathways. Deciphering TLR function in MM cells will help in understanding the mechanisms of tumor cell growth. In this study, we examined the response of MM cells to the MyD88-independent/TIR-domain-containing adapter-inducing IFN-β-dependent TLR3. Deregulation of NF-κB pathway is a feature of MM cells, and we wondered whether TLR3 activation could mobilize the NF-κB pathway. We show that five of seven human myeloma cell line (HMCL) cells expressed TLR3. In the presence of the synthetic TLR3 ligand (poly(I:C)), activation of NF-κB pathway was observed in three of five selected TLR3+ HMCL, NCI-H929, RPMI 8226, and KMM1. In agreement with NF-κB activation, only these three HMCL responded to poly(I:C), although by either an increase (KMM1) or a decrease (NCI-H929, RPMI 8226) of proliferation. We show that KMM1 increase of proliferation was prevented by NF-κB inhibitor. In contrast, inhibition of proliferation in both NCI-H929 and RPMI 8226 was due to IFN-α-induced apoptosis. We next demonstrated that p38 MAPK pathway controlled both IFN-α secretion and IFN-α-mediated cell death. Moreover, cell death also involved activation of ERK1/2 pathway. In conclusion, our results show that TLR3 ligand induces NF-κB pathway activation in MM and support a switching function of type I IFN in the functional outcome of TLR3 triggering in tumor cells.

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“…Furthermore, TRAIL resistance has been observed in many cancer cell types and various mechanisms including translocation of NF-B, and activation of PKB/Akt or Erk MAPK seem to be involved (17,20,21). These pathways can be induced by TLRs, including TLR9 (22)(23)(24), therefore jeopardizing the efficiency of the therapeutic use of TLR9 ligands. The aim of this work was to study the effects of CpG ODNs on TRAIL-induced cell death of tumors by using MM, colon, and breast cancer cell lines.…”

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confidence: 99%

Phosphorothioate-Modified TLR9 Ligands Protect Cancer Cells against TRAIL-Induced Apoptosis

Chiron

Pellat‐Deceunynck

Maillasson

et al. 2009

The Journal of Immunology

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Hypomethylated CpG oligodeoxynucleotides (CpG ODNs) target TLR9 expressed by immune cells and are currently being evaluated as adjuvants in clinical trials. However, TLR signaling can promote some tumor growth and immune evasion, such as in multiple myeloma (MM). Therefore, deciphering the effects of CpG ODNs on cancer cells will help in preventing these adverse effects and in designing future clinical trials. TLR activation induces multiple signaling pathways, notably NF-κB that has been involved in the resistance to TRAIL. Thus, we wondered if CpG ODNs could modulate TRAIL-induced apoptosis in different models of tumors. Here, we show that TLR9+ (NCI-H929, NAN6, KMM1) and TLR9− MM cells (MM1S) were protected by CpG ODNs against recombinant TRAIL-induced apoptosis. By using two fully human, agonist mAbs directed against TRAIL receptors DR4 and DR5 (mapatumumab and lexatumumab, respectively), we show that the protection was restricted to DR5-induced apoptosis. Similar results were observed for two colon cancer (C45 and Colo205) and two breast cancer cell lines (HCC1569 and Cal51). The protection of CpG ODNs was mediated by its nuclease-resistant phosphorothioate backbone independent of TLR9. We next demonstrated by surface plasmon resonance that phosphorothioate-modified CpG ODNs directly bound to either TRAIL or lexatumumab and then decreased their binding to DR5. Finally, NK cell lysis of a DR5-sensitive MM cell line (NCI-H929) through TRAIL was partially inhibited by phosphorothioate-modified CpG ODNs. In conclusion, our results suggest that the phosphorothioate modification of CpG ODNs could dampen the clinical efficacy of CpG ODN-based adjuvants by altering TRAIL/TRAIL receptor interaction.

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Collaborative Action of NF-κB and p38 MAPK Is Involved in CpG DNA-Induced IFN-α and Chemokine Production in Human Plasmacytoid Dendritic Cells

Cited by 71 publications

References 59 publications

A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

TLR3 Ligand Induces NF-κB Activation and Various Fates of Multiple Myeloma Cells Depending on IFN-α Production

Phosphorothioate-Modified TLR9 Ligands Protect Cancer Cells against TRAIL-Induced Apoptosis

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