TLR2 and the NLRP3 inflammasome mediate IL-1β production in Prevotella nigrescens-infected dendritic cells

Prevotella nigrescens is an oral pathogen that is frequently observed in the subgingival plaque of periodontitis patients. Interleukin-1β (IL-1β) is known to be involved in the immunopathology of periodontal diseases and has been implicated in the destruction of bone. In this study, we investigated the mechanism of IL-1β production by P. nigrescens in murine bone marrow-derived dendritic cells (BMDCs). Our results showed that a host receptor, Toll-like receptor 2 (TLR2), but not TLR4 is required for pro-IL-1β induction and nucleotide-binding oligomerization domain like receptor pyrin domain containing 3 (NLRP3) priming in BMDCs in response to P. nigrescens and activation of the NLRP3 inflammasome is necessary for processing of pro-IL-1β into mature IL-1β. In addition, an inhibitor assay revealed that production of reactive oxygen species, P2X₇R activity, and release of cathepsin B are involved in IL-1β production in BMDCs in response to P. nigrescens.     

Interleukin‐17A participates in podocyte injury by inducing IL‐1β secretion through ROS‐NLRP3 inflammasome‐caspase‐1 pathway

Studies show that the Th17/IL ‐17A axis plays an important role in the pathogenesis of kidney diseases. Previously, we also showed that IL ‐17A may play a role in the pathogenesis of primary nephrotic syndrome; however, the underlying mechanism(s) is unclear. The aim of this study was to explore the molecular mechanism of IL ‐17A‐inducing podocyte injury in vitro. In this study, the NLRP 3 inflammasome activation and the morphology of podocytes were detected by Western blot and immunofluorescence. The results showed that podocytes persistently expressed IL ‐17A receptor and that NLRP 3 inflammasome in these cells was activated upon exposure to IL ‐17A. Also, activity of caspase‐1 and secretion of IL ‐1β increased in the presence of IL ‐17A. In addition, IL ‐17A disrupted podocyte morphology by decreasing expression of podocin and increasing expression of desmin. Blockade of intracellular ROS or inhibition of caspase‐1 prevented activation of the NLRP 3 inflammasome, thereby restoring podocyte morphology. Taken together, the results suggest that IL ‐17A induces podocyte injury by activating the NLRP 3 inflammasome and IL ‐1β secretion and contributes to disruption of the kidney's filtration system.     

The stimulatory effect of α‐melanotropin on progesterone release from rat granulosa cells is inhibited by interleukin‐1β and by tumour necrosis factor‐α

Aim: Several studies have shown that a variety of peptides and cytokines are involved in ovarian regulatory mechanisms; however, their exact function is still unclear. In this work we study whether the administration of peptide α‐melanotropin and the cytokines interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNF‐α) on their own modify the release of progesterone in cultured granulosa cells (GC) from pro‐oestrous rats. We also investigate an interaction between these cytokines and α‐melanotropin in the modulation of progesterone secretion. Methods: Granulosa cells were collected from the ovaries of female Wistar rats and cultured for up to 24 h in the presence of different concentrations of α‐melanotropin, cytokines or a combination of both. Progesterone concentration was measured by radioimmunoassay. Results: The addition of α‐melanotropin in a dose of 0.01 and 0.1 mm had no effect on progesterone release, whereas a dose of 1 mm significantly increased progesterone release (P < 0.01) compared with the control culture. Progesterone release was not modified when different concentrations of interleukin‐1β or TNF‐α were added to the cell cultures. However, when interleukin‐1β or TNF‐α were added simultaneously with 1 μm α‐melanotropin, a significant reduction (P < 0.01 for interleukin‐1β and P < 0.05 for TNF‐α) of the steroid release was found with respect to the α‐melanotropin‐treated group. Conclusions: These results lead us to suggest that, although α‐melanotropin stimulates progesterone release in pre‐ovulatory GC, this effect is blocked by the presence of interleukin‐1β or TNF‐α.     

The Cag pathogenicity island and interaction between TLR2/NOD2 and NLRP3 regulate IL‐1β production in Helicobacter pylori infected dendritic cells

Helicobacter pylori colonization of the stomach affects about half of the world population and is associated with the development of gastritis, ulcers, and cancer. Polymorphisms in the IL1B gene are linked to an increased risk of H. pylori associated cancer, but the bacterial and host factors that regulate interleukin (IL)‐1β production in response to H. pylori infection remain unknown. Using murine BM‐derived DCs, we show that the bacterial virulence factors cytotoxin‐associated genes pathogenicity island and CagL, but not vacuolating cytotoxin A or CagA, regulate the induction of pro‐IL‐1β and the production of mature IL‐1β in response to H. pylori infection. We further show that the host receptors, Toll‐like receptor 2 (TLR2) and nucleotide‐binding oligomerization domain 2 (NOD2), but not NOD1, are required for induction of pro‐IL‐1β and NOD‐like receptor pyrin domain containing 3 (NLRP3) in H. pylori infected DCs. In contrast, NLRP3 and the adaptor ASC were essential for the activation of caspase‐1, processing of pro‐IL‐1β into IL‐1β, and IL‐1β secretion. Finally, we show that mice deficient in caspase‐1, IL‐1β, and IL‐1 receptor, but not NLRP3, are impaired in the clearance of CagA‐positive H. pylori from the stomach when compared with WT mice. These studies identify bacterial cag pathogenicity island and the cooperative interaction among host innate receptors TLR2, NOD2, and NLRP3 as important regulators of IL‐1β production in H. pylori infected DCs.     

Galectin‐3 is an amplifier of the interleukin‐1β‐mediated inflammatory response in corneal keratinocytes

Interleukin‐1β (IL‐1β) is a potent mediator of innate immunity commonly up‐regulated in a broad spectrum of inflammatory diseases. When bound to its cell surface receptor, IL‐1β initiates a signalling cascade that cooperatively induces the expression of canonical IL‐1 target genes such as IL‐8 and IL‐6. Here, we present galectin‐3 as a novel regulator of IL‐1β responses in corneal keratinocytes. Using the SNAP‐tag system and digitonin semi‐permeabilization, we show that recombinant exogenous galectin‐3 binds to the plasma membrane of keratinocytes and is internalized into cytoplasmic compartments. We find that exogenous galectin‐3, but not a dominant negative inhibitor of galectin‐3 polymerization lacking the N‐terminal domain, exacerbates the response to IL‐1β by stimulating the secretion of inflammatory cytokines. The activity of galectin‐3 could be reduced by a novel d ‐galactopyranoside derivative targeting the conserved galactoside‐binding site of galectins and did not involve interaction with IL‐1 receptor 1 or the induction of endogenous IL‐1β. Consistent with these observations, we demonstrate that small interfering RNA‐mediated suppression of endogenous galectin‐3 expression is sufficient to impair the IL‐1β‐induced secretion of IL‐8 and IL‐6 in a p38 mitogen‐activated protein kinase‐independent manner. Collectively, our findings provide a novel role for galectin‐3 as an amplifier of IL‐1β responses during epithelial inflammation through an as yet unidentified mechanism.     

Effect of enterohaemorrhagic Escherichia coli O157:H7‐specific enterohaemolysin on interleukin‐1β production differs between human and mouse macrophages due to the different sensitivity of NLRP3 activation

Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 infection in humans can cause acute haemorrhagic colitis and severe haemolytic uraemic syndrome. The role of enterohaemolysin (Ehx) in the pathogenesis of O157:H7‐mediated disease in humans remains undefined. Recent studies have revealed the importance of the inflammatory response in O157:H7 pathogenesis in humans. We previously reported that Ehx markedly induced interleukin‐1β (IL‐1β) production in human macrophages. Here, we investigated the disparity in Ehx‐induced IL‐1β production between human and mouse macrophages and explored the underlying mechanism regarding the activation of NOD‐like receptor family, pyrin domain containing 3 (NLRP3) inflammasomes. In contrast to the effects on human differentiated THP‐1 cells and peripheral blood mononuclear cells, Ehx exerted no effect on IL‐1β production in mouse macrophages and splenocytes because of a disparity in pro‐IL‐1β cleavage into mature IL‐1β upon caspase‐1 activation. Additionally, Ehx significantly contributed to O157:H7‐induced ATP release from THP‐1 cells, which was not detected in mouse macrophages. Confocal microscopy demonstrated that Ehx was a key inducer of cathepsin B release in THP‐1 cells but not in mouse IC‐21 cells upon O157:H7 challenge. Inhibitor experiments indicated that O157:H7‐induced IL‐1β production was largely dependent upon caspase‐1 activation and partially dependent upon ATP signalling and cathepsin B release, which were both involved in NLRP3 activation. Moreover, inhibition of K⁺ efflux drastically diminished O157:H7‐induced IL‐1β production and cytotoxicity. The findings in this study may shed light on whether and how the Ehx contributes to the development of haemolytic uraemic syndrome in human O157:H7 infection.     

Impaired NLRP3 inflammasome activity during fetal development regulates IL‐1β production in human monocytes

Interleukin‐1β (IL‐1β) production is impaired in cord blood monocytes. However, the mechanism underlying this developmental attenuation remains unclear. Here, we analyzed the extent of variability within the Toll‐like receptor (TLR)/NLRP3 inflammasome pathways in human neonates. We show that immature low CD14 expressing/CD16^pos monocytes predominate before 33 weeks of gestation, and that these cells lack production of the pro‐IL‐1β precursor protein upon LPS stimulation. In contrast, high levels of pro‐IL‐1β are produced within high CD14 expressing monocytes, although these cells are unable to secrete mature IL‐1β. The lack of secreted IL‐1β in these monocytes parallels a reduction of NLRP3 induction following TLR stimulation resulting in a lack of caspase‐1 activity before 29 weeks of gestation, whereas expression of the apoptosis‐associated speck‐like protein containing a CARD and function of the P2×7 receptor are preserved. Our analyses also reveal a strong inhibitory effect of placental infection on LPS/ATP‐induced caspase‐1 activity in cord blood monocytes. Lastly, secretion of IL‐1β in preterm neonates is restored to adult levels during the neonatal period, indicating rapid maturation of these responses after birth. Collectively, our data highlight important developmental mechanisms regulating IL‐1β responses early in gestation, in part due to a downregulation of TLR‐mediated NLRP3 expression. Such mechanisms may serve to limit potentially damaging inflammatory responses in a developing fetus.     

Synovial macrophage‐derived IL‐1β regulates the calcitonin receptor in osteoarthritic mice

Recent studies have reported that calcitonin gene‐related peptide (CGRP) contributes to joint pain. However, regulation of the CGRP/CGRP receptor signalling in osteoarthritis (OA) is not fully understood. To investigate the regulation of CGRP/CGRP receptor signalling by macrophages in the synovial tissue (ST) of OA joints, we characterized the gene expression profiles of CGRP and CGRP receptors in the ST of OA mice (STR/Ort). In addition, we examined whether macrophage depletion by the systemic injection of clodronate‐laden liposomes affected the expression of CGRP and CGRP receptors in ST. CD11c⁺ macrophages in the ST of STR/Ort and C57BL/6J mice were analysed by flow cytometry. Real‐time polymerase chain reaction (PCR) was used to evaluate the expression of interleukin (IL)‐1β, CGRP, calcitonin receptor‐like receptor (CLR) and receptor activity‐modifying protein 1 (RAMP1) in F4/80⁺ and F4/80^? cells. The effects of IL‐1β on the expression of CGRP and CLR by cultured synovial cells were also examined. The percentage of CD11c⁺ macrophages in the ST of STR/Ort was higher than that in C57/BL6J mice. Notably, the F4/80⁺ cell fraction expressed IL‐1β highly, whereas the F4/80^? cell fraction expressed CGRP, CLR, and RAMP1 highly. In addition, expression of the IL‐1β and CLR genes was increased in ST, but was decreased upon macrophage depletion, and the IL‐1β treatment of cultured synovial cells up‐regulated CLR. Taken together, the present findings suggest that synovial macrophages are the major producers of IL‐1β and regulators of CLR in OA mice. Therefore, macrophages and IL‐1β may be suitable therapeutic targets for treating OA pain.     

The Nlrp3 inflammasome,IL‐1β, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL/6 mice

Infection of C57BL/6 mice with most Leishmania major strains results in a healing lesion and clearance of parasites from the skin. Infection of C57BL/6 mice with the L. major Seidman strain (LmSd), isolated from a patient with chronic lesions, despite eliciting a strong Th1 response, results in a nonhealing lesion, poor parasite clearance, and complete destruction of the ear dermis. We show here that in comparison to a healing strain, LmSd elicited early upregulation of IL‐1β mRNA and IL‐1β‐producing dermal cells and prominent neutrophil recruitment to the infected skin. Mice deficient in Nlrp3, apoptosis‐associated speck‐like protein containing a caspase recruitment domain, or caspase‐1/11, or lacking IL‐1β or IL‐1 receptor signaling, developed healing lesions and cleared LmSd from the infection site. Mice resistant to LmSd had a stronger antigen‐specific Th1 response. The possibility that IL‐1β might act through neutrophil recruitment to locally suppress immunity was supported by the healing observed in neutropenic Genista mice. Secretion of mature IL‐1β by LmSd‐infected macrophages in vitro was dependent on activation of the Nlrp3 inflammasome and caspase‐1. These data reveal that Nlrp3 inflammasome‐dependent IL‐1β, associated with localized neutrophil recruitment, plays a crucial role in the development of a nonhealing form of cutaneous leishmaniasis in conventionally resistant mice.     

Interleukin‐17‐producing γδ+ T cells protect NOD mice from type 1 diabetes through a mechanism involving transforming growth factor‐β

Whether interleukin (IL)‐17 promotes a diabetogenic response remains unclear. Here we examined the effects of neutralization of IL‐17 on the progress of adoptively transferred diabetes. IL‐17‐producing cells in non‐obese diabetic (NOD) mice were identified and their role in the pathogenesis of diabetes examined using transfer and co‐transfer assays. Unexpectedly, we found that in vivo neutralization of IL‐17 did not protect NOD–severe combined immunodeficiency (SCID) mice against diabetes transferred by diabetic splenocytes. In NOD mice, γδ⁺ T cells were dominated by IL‐17‐producing cells and were found to be the major source of IL‐17. Interestingly, these IL‐17‐producing γδ T cells did not exacerbate diabetes in an adoptive transfer model, but had a regulatory effect, protecting NOD mice from diabetes by up‐regulating transforming growth factor (TGF)‐β production. Our data suggest that the presence of IL‐17 did not increase the chance of the development of diabetes; γδ T cells protected NOD mice from diabetes in a TGF‐β‐dependent manner, irrespective of their role as major IL‐17 producers.     

Hypoxia inducible factor‐1α‐induced interleukin‐33 expression in intestinal epithelia contributes to mucosal homeostasis in inflammatory bowel disease

Intestinal epithelial cells (IECs), an important barrier to gut microbiota, are subject to low oxygen tension, particularly during intestinal inflammation. Hypoxia inducible factor‐1α (HIF‐1α) is expressed highly in the inflamed mucosa of inflammatory bowel disease (IBD) and functions as a key regulator in maintenance of intestinal homeostasis. However, how IEC‐derived HIF‐1α regulates intestinal immune responses in IBD is still not understood completely. We report here that the expression of HIF‐1α and IL‐33 was increased significantly in the inflamed mucosa of IBD patients as well as mice with colitis induced by dextran sulphate sodium (DSS). The levels of interleukin (IL)?33 were correlated positively with that of HIF‐1α. A HIF‐1α‐interacting element was identified in the promoter region of IL‐33, indicating that HIF‐1α activity regulates IL‐33 expression. Furthermore, tumour necrosis factor (TNF) facilitated the HIF‐1α‐dependent IL‐33 expression in IEC. Our data thus demonstrate that HIF‐1α‐dependent IL‐33 in IEC functions as a regulatory cytokine in inflamed mucosa of IBD, thereby regulating the intestinal inflammation and maintaining mucosal homeostasis.     

Mechanism of interleukin‐1β‐induced proliferation in rat hepatic stellate cells from different levels of signal transduction

Hepatic stellate cells (HSCs) are the major producers of collagen in the liver. Their conversion from resting cells to proliferative, contractile, and activated cells is a critical step leading to liver fibrosis that is characterized by the deposition of excessive extracellular matrix. Interleukin‐1 (IL‐1) may play a role in maintaining HSC in a proliferative state that is responsible for hepatic fibrogenesis. The aim of this study was to study the roles of the IL‐1 type I receptor (IL‐1R1), c‐Jun N‐terminal kinase (JNK), and activation protein‐1 (AP‐1) in IL‐1β–mediated proliferation in rat HSCs. We showed that IL‐1β can upregulate proliferation in rat HSCs; however, inhibition of the JNK pathway could inhibit HSCs proliferation. Furthermore, IL‐1β activated IL‐1R1 expression, the JNK signaling pathway, and AP‐1 activity in a time‐dependent manner in rat HSCs. These data demonstrate that IL‐1β could promote the proliferation of rat HSCs and that the IL‐1R1, JNK, and AP‐1 pathways were involved in this process. In summary, IL‐1β‐induced proliferation is possibly mediated by the IL‐1R1, JNK, and AP‐1 pathways in rat HSCs. Therefore, drugs that block these pathways may inhibit the proliferation of HSCs and suppress liver fibrosis.     

Synergistic effect of interleukin‐17 and tumour necrosis factor‐α on inflammatory response in hepatocytes through interleukin‐6‐dependent and independent pathways

The proinflammatory cytokines interleukin (IL)‐17 and tumour necrosis factor (TNF)‐α are targets for treatment in many chronic inflammatory diseases. Here, we examined their role in liver inflammatory response compared to that of IL‐6. Human hepatoma cells (HepaRG, Huh7.5 and HepG2 cells) and primary human hepatocytes (PHH) were cultured with IL‐6, IL‐17 and/or TNF‐α. To determine the contribution of the IL‐6 pathway in the IL‐17/TNF‐α‐mediated effect, an anti‐IL‐6 receptor antibody was used. IL‐17 and TNF‐α increased in synergy IL‐6 secretion by HepaRG cells and PHH but not by Huh7.5 and HepG2 cells. This IL‐17/TNF‐α synergistic cooperation enhanced the levels of C‐reactive protein (CRP) and aspartate aminotransferase (ASAT) in HepaRG cell and PHH cultures through the induction of IL‐6. IL‐17/TNF‐α also up‐regulated IL‐8, monocyte chemoattractant protein (MCP)‐1 and chemokine (C‐C motif) ligand 20 (CCL20) chemokines in synergy through an IL‐6‐independent pathway. Interestingly, first exposure to IL‐17, but not to TNF‐α, was crucial for the initiation of the IL‐17/TNF‐α synergistic effect on IL‐6 and IL‐8 production. In HepaRG cells, IL‐17 enhanced IL‐6 mRNA stability resulting in increased IL‐6 protein levels. The IL‐17A/TNF‐α synergistic effect on IL‐6 and IL‐8 induction was mediated through the activation of extracellular signal‐regulated kinase (ERK)‐mitogen‐activated protein kinase, nuclear factor‐κB and/or protein kinase B (Akt)–phosphatidylinositol 3‐kinase signalling pathways. Therefore, the IL‐17/TNF‐α synergistic interaction mediates systemic inflammation and cell damage in hepatocytes mainly through IL‐6 for CRP and ASAT induction. Independently of IL‐6, the IL‐17A/TNF‐α combination may also induce immune cell recruitment by chemokine up‐regulation. IL‐17 and/or TNF‐α neutralization can be a promising therapeutic strategy to control both systemic inflammation and liver cell attraction.     

Interferon‐γ constrains cytokine production of group 2 innate lymphoid cells

Group 2 innate lymphoid cells (ILC2s) produce a significant amount of interleukin‐5 (IL‐5), which supports eosinophil responses in various tissues; they also produce IL‐13, which induces mucus production and contributes to tissue repair or fibrosis. The ILC2s are activated by alarmins, such as IL‐33 released from epithelia, macrophages and natural killer T (NKT) cells in response to infection and allergen exposure, leading to epithelial injury. We examined gene expression in lung ILC2s and found that ILC2s expressed Ifngr1, the receptor for interferon‐γ (IFN‐γ). Interferon‐γ severely inhibited IL‐5 and IL‐13 production by lung and kidney ILC2s. To evaluate the effects in vivo, we used α‐galactosylceramide (α‐GalCer) to induce NKT cells to produce IL‐33 and IFN‐γ. Intraperitoneal injection of α‐GalCer in mice induced NKT cell activation resulting in IL‐5 and IL‐13 production by ILC2s. Administration of anti‐IFN‐γ together with α‐GalCer significantly enhanced the production of IL‐5 and IL‐13 by ILC2s in lung and kidney. Conversely, cytokine production from ILC2s was markedly suppressed after injection of exogenous IL‐33 in Il33^?/? mice pre‐treated with α‐GalCer. Hence, IFN‐γ induced or already present in tissues can impact downstream pleiotropic functions mediated by ILC2s, such as inflammation and tissue repair.     

Caspase‐4 mediates non‐canonical activation of the NLRP3 inflammasome in human myeloid cells

Inflammasome activation culminates in activation of caspase‐1, which leads to the maturation and subsequent release of cytokines of the interleukin 1 (IL‐1) family and results in a particular form of cell death known as pyroptosis. In addition, in the murine system, a so‐called non‐canonical inflammasome involving caspase‐11 has been described that directly responds to cytosolic LPS. Here, we show that the human monocytic cell line THP1 activates the inflammasome in response to cytosolic LPS in a TLR4‐independent fashion. This response is mediated by caspase‐4 and accompanied by caspase‐1 activation, pyroptosis, and IL‐1β maturation. In addition to caspase‐4, efficient IL‐1β conversion upon intracellular LPS delivery relies on potassium efflux, NLRP3, ASC, and caspase‐1, indicating that although caspase‐4 activation alone is sufficient to induce pyroptosis, this process depends on the NLRP3 inflammasome activation to drive IL‐1β maturation. Altogether, this study provides evidence for the presence of a non‐canonical inflammasome in humans and its dependence on caspase‐4.     

The NLRP3 inflammasome: A sensor of immune danger signals

The innate immune system senses danger signals via evolutionary conserved receptors. The nucleotide-binding domain leucine-rich repeat containing receptor (NLR) family is a group of intracellular receptors that drive a wide variety of inflammatory responses. A number of the NLR family members can form inflammasomes, which are multiprotein complexes that can activate caspase-1 and ultimately lead to the processing and secretion of interleukin (IL)-1β, IL-18 and IL-33. One of the best-studied members of the NLR family is NLRP3 for which a number of divergent activators have recently been described. These and other studies examining the NLRP3 inflammasome will be discussed in this review.     

Mechanisms of chorioamnionitis‐associated preterm birth: interleukin‐1β inhibits progesterone receptor expression in decidual cells

In chorioamnionitis (CAM), a major cause of preterm birth (PTB), maternal–fetal inflammation of the decidua and amniochorion cause the release of cytokines that elicit cervical ripening, fetal membrane rupture and myometrial activation. We posit that this inflammatory milieu triggers PTB by inhibiting progesterone receptor (PR) expression and increasing decidual prostaglandin (PG) production. Immunohistochemical staining of decidua detected significantly lower PR levels in decidual cells (DCs) from CAM‐complicated PTB. Incubation of DCs with IL‐1β decreased PR expression and significantly increased PGE₂ and PGF_2α production and COX‐2 expression. The addition of PGF_2α to DC cultures also suppressed PR expression. However, the COX inhibitor, indomethacin, did not reverse IL‐1β suppression of PR expression in DC cultures. Although IL‐1β treatment activated the NF‐K B, ERK1/2 and p38 MAPK signalling cascades in DCs, inhibition of ERK1/2 MAPK signalling alone was sufficient to completely reverse the suppression of PR levels by IL‐1β. These findings suggest that CAM‐associated PTB is induced at least in part by IL‐1β‐mediated functional progesterone withdrawal. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

TSLP production by dendritic cells is modulated by IL‐1β and components of the endoplasmic reticulum stress response

Thymic stromal lymphopoietin (TSLP) produced by epithelial cells acts on dendritic cells (DCs) to drive differentiation of T_H2‐cells, and is therefore important in allergic disease pathogenesis. However, DCs themselves make significant amounts of TSLP in response to microbial products, but little is known about the key downstream signals that induce and modulate this TSLP secretion from human DCs. We show that human monocyte derived DC (mDC) secretion of TSLP in response to Candida albicans and β‐glucans requires dectin‐1, Syk, NF‐κB, and p38 MAPK signaling. In addition, TSLP production by mDCs is greatly enhanced by IL‐1β, but not TNF‐α, in contrast to epithelial cells. Furthermore, TSLP secretion is significantly increased by signals emanating from the endoplasmic reticulum (ER) stress response, specifically the unfolded protein response sensors, inositol‐requiring transmembrane kinase/endonuclease 1 and protein kinase R‐like ER kinase, which are activated by dectin‐1 stimulation. Thus, TSLP production by mDCs requires the integration of signals from dectin‐1, the IL‐1 receptor, and ER stress signaling pathways. Autocrine TSLP production is likely to play a role in mDC‐controlled immune responses at sites removed from epithelial cell production of the cytokine, such as lymphoid tissue.