[Immune Regulation by TNF Receptor-associated Factor 5].

The tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family of molecules are intracellular adaptors that regulate cellular signaling through members of the TNFR and Toll-like receptor superfamily. Mammals have seven TRAF molecules numbered sequentially from TRAF1 to TRAF7. Although TRAF5 was identified as a potential regulator of TNFR superfamily members, the in vivo function of TRAF5 has not yet been fully elucidated. We identified an unconventional role of TRAF5 in interleukin-6 (IL-6) receptor signaling involving CD4+ T cells. Moreover, TRAF5 binds to the signal-transducing glycoprotein 130 (gp130) receptor for IL-6 and inhibits the activity of the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. In addition, Traf5-deficient CD4+ T cells exhibit significantly enhanced IL-6-driven differentiation of T helper 17 (Th17) cells, which exacerbates neuroinflammation in experimental autoimmune encephalomyelitis. Furthermore, TRAF5 demonstrates a similar activity to gp130 for IL-27, another cytokine of the IL-6 family. Additionally, Traf5-deficient CD4+ T cells display significantly increased IL-27-mediated differentiation of Th1 cells, which increases footpad swelling in delayed-type hypersensitivity response. Thus, TRAF5 functions as a negative regulator of gp130 in CD4+ T cells. This review aimed to explain how TRAF5 controls the differentiation of CD4+ T cells and discuss how the expression of TRAF5 in T cells and other cell types can influence the development and progression of autoimmune and inflammatory diseases.

Interleukin-6 signalling in health and disease.

Biochemically, interleukin-6 belongs to the class of four-helical cytokines. The cytokine can be synthesised and secreted by many cells. It acts via a cell surface-expressed interleukin-6 receptor, which is not signalling competent. This receptor, when complexed with interleukin-6, associates with the signalling receptor glycoprotein 130 kDa (gp130), which becomes dimerised and initiates intracellular signalling via the Janus kinase/signal transducer and activator of transcription and rat sarcoma proto oncogene/mitogen-activated protein kinase/phosphoinositide-3 kinase pathways. Physiologically, interleukin-6 is involved in the regulation of haematopoiesis and the coordination of the innate and acquired immune systems. Additionally, interleukin-6 plays an important role in the regulation of metabolism, in neural development and survival, and in the development and maintenance of various cancers. Although interleukin-6 is mostly regarded as a pro-inflammatory cytokine, there are numerous examples of protective and regenerative functions of this cytokine. This review will explain the molecular mechanisms of the, in part opposing, activities of the cytokine interleukin-6.

Role of Interleukin-6 in Lung Complications in Patients With COVID-19: Therapeutic Implications.

COVID-19 is viral respiratory infection with frequently fatal lung complications in the elderly or in people with serious comorbidities. Lung destruction appears to be associated with a cytokine storm related to an increased level of interleukin-6 (IL6). Therapeutic targeting of the interleukin-6 signaling pathway can attenuate such a cytokine storm and can be beneficial for patients with COVID-19 in danger of pulmonary failure. This article demonstrates the importance of IL6 in progression of disease and the possibility of inhibition of IL6 signaling in COVID-19 therapy.

Cd9 Protects Photoreceptors from Injury and Potentiates Edn2 Expression.

Purpose: Cd9 is a tetraspanin membrane protein that plays various roles in tissue development and disease pathogenesis, especially in cancer, but the expression patterns and function of Cd9 in retinal development and disease are not well understood. We asked its roles during retinal photoreceptor degeneration by using CD9-knockout mice. Methods: Cd9 knockout mice and rd1 mice were used to examine roles of Cd9 for progression of photoreceptor degeneration. Reverse transcription-polymerase chain reaction and immunohistochemistry were mainly used as analytical methods. Results: Cd9 transcripts were only weakly expressed in retina at embryonic day 14, but its expression level subsequently increased and peaked at around postnatal day 12. In 6-week-old female mice derived retina, mRNA expression decreased slightly but was maintained at a significant level. Published RNA-sequencing data and immunohistochemistry indicated that Cd9 was expressed abundantly in Müller glia and weakly in other retinal neurons. Notably, when photoreceptors were damaged, Cd9 expression was increased in rod photoreceptors and decreased in Müller glia. Cd9 knockout mice retinas developed normally; however, once the retina suffered damage, degeneration of photoreceptors was more severe in Cd9 knockout retinas than control retinas. Induction of Edn2, which is known to protect against photoreceptor damage, was severely hampered. In addition, induction of Socs3, which is downstream of gp130 (Il6st), was weaker in Cd9 knockout retinas. Conclusions: Taken together, these findings indicate that, although Cd9 was dispensable for normal gross morphological development, it protected rod photoreceptors and enhanced Edn2 expression, possibly through modulation of gp130 signaling.

Role of gp130 in basal and exercise-trained skeletal muscle mitochondrial quality control.

The IL-6 cytokine family activates intracellular signaling pathways through glycoprotein-130 (gp130), and this signaling has established regulatory roles in muscle glucose metabolism and proteostasis. Although the IL-6 family has been implicated as myokines regulating the muscles' metabolic response to exercise, gp130's role in mitochondrial quality control involving fission, fusion, mitophagy, and biogenesis is not well understood. Therefore, we examined gp130's role in basal and exercise-trained muscle mitochondrial quality control. Muscles from C57BL/6, skeletal muscle-specific gp130 knockout (KO) mice, and C2C12 myotubes, were examined. KO did not alter treadmill run-to-fatigue or indices of mitochondrial content [cytochrome- c oxidase (COX) activity] or biogenesis (AMPK, peroxisome proliferator-activated receptor-γ coactivator-1α, mitochondrial transcription factor A, and COX IV). KO increased mitochondrial fission 1 protein (FIS-1) while suppressing mitofusin-1 (MFN-1), which was recapitulated in myotubes after gp130 knockdown. KO induced ubiquitin-binding protein p62, Parkin, and ubiquitin in isolated mitochondria from gastrocnemius muscles. Knockdown of gp130 in myotubes suppressed STAT3 and induced accumulation of microtubule-associated protein-1 light chain 3B (LC3)-II relative to LC3-I. Suppression of myotube STAT3 did not alter FIS-1 or MFN-1. Exercise training increased muscle gp130 and suppressed STAT3. KO did not alter the exercise-training induction of COX activity, biogenesis, FIS-1, or Beclin-1. KO increased MFN-1 and suppressed 4-hydroxynonenal after exercise training. These findings suggest a role for gp130 in the modulation of mitochondrial dynamics and autophagic processes. NEW & NOTEWORTHY Although the IL-6 family of cytokines has been implicated in the regulation of skeletal muscle protein turnover and metabolism, less is understood about its role in mitochondrial quality control. We examined the glycoprotein-130 receptor in the regulation of skeletal muscle mitochondria quality control in the basal and exercise-trained states. We report that the muscle glycoprotein-130 receptor modulates basal mitochondrial dynamics and autophagic processes and is not necessary for exercise-training mitochondrial adaptations to quality control.

Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism.

Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature IL18, but not IL1ß, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1ß and IL1α activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1ß, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer.Significance: Inflammasome activation that elevates IL18 helps drive gastric cancer by protecting cancer cells against apoptosis, with potential implications for new therapeutic strategies in this setting. Cancer Res; 78(5); 1293-307. ©2017 AACR.

A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis.

Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.

Hyper-IL-6: a potent and efficacious stimulator of RGC regeneration.

Mature retinal ganglion cells (RGCs) normally fail to regenerate injured axons and die soon after optic nerve injury. Research over the last two decades has demonstrated that application of IL-6-like cytokines or activation of respective downstream signaling pathways promote neuroprotection and optic nerve regeneration. However, the overall beneficial effects of natural cytokines remain usually rather moderate, possibly due to intrinsic signaling pathway inhibitors, such as PTEN or SOCS3, or a limited expression of specific cytokine receptors in RGCs. It was recently demonstrated that directly targeting the gp130 receptor, a common signalling receptor of all IL-6-like cytokines, induces stronger RGC axon regeneration in vitro and in vivo than other known growth-promoting treatments such as inflammatory stimulation or PTEN knockout. Remarkably, continuous expression of hyper-IL-6 (hIL-6) upon intravitreal AAV injection after nerve injury enables long-distance axon regeneration, with some axons growing through the optic chiasm 6 weeks after optic nerve injury. Thus, AAV-mediated hIL-6 delivery is so far one of the strongest single, post-injury treatments for the promotion of optic nerve regeneration and may be suitable for the development of novel, clinically applicable therapeutic treatments for human patients.

Constitutive gp130 activation rapidly accelerates the transformation of human hepatocytes via an impaired oxidative stress response.

Pro-inflammatory signaling pathways, especially interleukin 6 (IL-6), and reactive oxygen species (ROS) promote carcinogenesis in the liver. In order to elucidate the underlying oncogenic mechanism, we activated the IL-6 signal transducer glycoprotein 130 (gp130) via stable expression of a constitutively active gp130 construct (L-gp130) in untransformed telomerase-immortalized human fetal hepatocytes (FH-hTERT). As known from hepatocellular adenomas, forced gp130 activation alone was not sufficient to induce malignant transformation. However, additional challenge of FH-hTERT L-gp130 clones with oxidative stress resulted in 2- to 3-fold higher ROS levels and up to 6-fold more DNA-double strand breaks (DSB). Despite increased DNA damage, ROS-challenged FH-hTERT L-gp130 clones displayed an enhanced proliferation and rapidly developed colony growth capabilities in soft agar. As driving gp130-mediated oncogenic mechanism, we detected a decreased expression of antioxidant genes, in particular glutathione peroxidase 3 and apolipoprotein E, and an absence of P21 upregulation following ROS-conferred induction of DSB. In summary, an impaired oxidative stress response in hepatocytes with gp130 gain-of-function mutations, as detected in dysplastic intrahepatic nodules and hepatocellular adenomas, is one of the central oncogenic mechanisms in chronic liver inflammation.

gp130 in late osteoblasts and osteocytes is required for PTH-induced osteoblast differentiation.

Parathyroid hormone (PTH) treatment stimulates osteoblast differentiation and bone formation, and is the only currently approved anabolic therapy for osteoporosis. In cells of the osteoblast lineage, PTH also stimulates the expression of members of the interleukin 6 (IL-6) cytokine superfamily. Although the similarity of gene targets regulated by these cytokines and PTH suggest cooperative action, the dependence of PTH anabolic action on IL-6 cytokine signaling is unknown. To determine whether cytokine signaling in the osteocyte through glycoprotein 130 (gp130), the common IL-6 superfamily receptor subunit, is required for PTH anabolic action, male mice with conditional gp130 deletion in osteocytes (Dmp1Cre.gp130(f/f)) and littermate controls (Dmp1Cre.gp130(w/w)) were treated with hPTH(1-34) (30 µg/kg 5× per week for 5 weeks). PTH dramatically increased bone formation in Dmp1Cre.gp130(w/w) mice, as indicated by elevated osteoblast number, osteoid surface, mineralizing surface, and increased serum N-terminal propeptide of type 1 collagen (P1NP). However, in mice with Dmp1Cre-directed deletion of gp130, PTH treatment changed none of these parameters. Impaired PTH anabolic action was associated with a 50% reduction in Pth1r mRNA levels in Dmp1Cre.gp130(f/f) femora compared with Dmp1Cre.gp130(w/w). Furthermore, lentiviral-Cre infection of gp130(f/f) primary osteoblasts also lowered Pth1r mRNA levels to 16% of that observed in infected C57/BL6 cells. In conclusion, osteocytic gp130 is required to maintain PTH1R expression in the osteoblast lineage, and for the stimulation of osteoblast differentiation that occurs in response to PTH.

Human herpesvirus 8 viral interleukin-6 signaling through gp130 promotes virus replication in primary effusion lymphoma and endothelial cells.

The contributions of human herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6) to virus biology remain unclear. Here we examined the role of vIL-6/gp130 signaling in HHV-8 productive replication in primary effusion lymphoma and endothelial cells. Depletion and depletion-complementation experiments revealed that endoplasmic reticulum-localized vIL-6 activity via gp130 and gp130-activated signal transducer and activator of transcription (STAT) signaling, but not extracellular signal-regulated kinase (ERK) activation, was critical for vIL-6 proreplication activity. Our data significantly extend current understanding of vIL-6 function and associated mechanisms in HHV-8 biology.

The p38-mediated rapid down-regulation of cell surface gp130 expression impairs interleukin-6 signaling in the synovial fluid of juvenile idiopathic arthritis patients.

OBJECTIVE: Interleukin-6 (IL-6) signaling plays an important proinflammatory role, but this role is restricted by regulatory mechanisms that, for example, reduce the cell surface availability of the signal-transducing chain of the IL-6 receptor, gp130. The aim of this study was to determine whether the inflammatory environment in arthritic joints has an impact on monocytic gp130 surface expression and the extent to which regulatory processes in the synovial fluid (SF) can be reproduced in an in vitro model. METHODS: Flow cytometry and live cell imaging were used to measure the cell surface expression and internalization of gp130. STAT-3 phosphorylation was monitored by flow cytometry and Western blotting. RESULTS: In patients with juvenile idiopathic arthritis (JIA), levels of cell surface gp130 expression in SF monocytes were reduced compared to those in peripheral blood (PB) monocytes. These reduced levels were reproduced when PB monocytes from healthy donors were stimulated with SF, and this reduction was dependent on p38 MAPK. The induction of p38 by IL-1ß in PB monocytes interfered with IL-6 signaling due to the reduced cell surface expression of gp130. CONCLUSION: These results suggest that p38-mediated proinflammatory stimuli induce the down-regulation of gp130 on monocytes and thus restrict gp130-mediated signal transduction. This regulatory mechanism could be of relevance to processes in the inflamed joints of patients with JIA.

Elevated CXCL1 expression in gp130-deficient endothelial cells impairs neutrophil migration in mice.

Neutrophils emigrate from venules to sites of infection or injury in response to chemotactic gradients. How these gradients form is not well understood. Some IL-6 family cytokines stimulate endothelial cells to express adhesion molecules and chemokines that recruit leukocytes. Receptors for these cytokines share the signaling subunit gp130. We studied knockout mice lacking gp130 in endothelial cells. Unexpectedly, gp130-deficient endothelial cells constitutively expressed more CXCL1 in vivo and in vitro, and even more upon stimulation with tumor necrosis factor-α. Mobilization of this increased CXCL1 from intracellular stores to the venular surface triggered ß2 integrin-dependent arrest of neutrophils rolling on selectins but impaired intraluminal crawling and transendothelial migration. Superfusing CXCL1 over venules promoted neutrophil migration only after intravenously injecting mAb to CXCL1 to diminish its intravascular function or heparinase to release CXCL1 from endothelial proteoglycans. Remarkably, mice lacking gp130 in endothelial cells had impaired histamine-induced venular permeability, which was restored by injecting anti-P-selectin mAb to prevent neutrophil rolling and arrest. Thus, excessive CXCL1 expression in gp130-deficient endothelial cells augments neutrophil adhesion but hinders migration, most likely by disrupting chemotactic gradients. Our data define a role for endothelial cell gp130 in regulating integrin-dependent adhesion and de-adhesion of neutrophils during inflammation.

Stress in the adult rat exacerbates muscle pain induced by early-life stress.

BACKGROUND: Early-life stress and exposure to stressful stimuli play a major role in the development of chronic widespread pain in adults. However, how they interact in chronic pain syndromes remains unclear. METHODS: Dams and neonatal litters were submitted to a restriction of nesting material (neonatal limited bedding [NLB]) for 1 week. As adults, these rats were exposed to a painless sound stress protocol. The involvement of sympathoadrenal catecholamines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) in nociception was evaluated through behavioral and enzyme-linked immunosorbent assays, surgical interventions, and intrathecal antisense treatments. RESULTS: Adult NLB rats exhibited mild muscle hyperalgesia, which was markedly aggravated by sound stress (peaking 15 days after exposure). Adrenal medullectomy did not modify hyperalgesia in NLB rats but prevented its aggravation by sound stress. Sustained administration of epinephrine to NLB rats mimicked sound stress effect. Intrathecal treatment with antisense directed to IL-6 receptor subunit gp130 (gp130), but not to tumor necrosis factor receptor type 1 (TNFR1), inhibited hyperalgesia in NLB rats. However, antisense against either gp130 or TNFR1 inhibited sound stress-induced enhancement of hyperalgesia. Compared with control rats, NLB rats exhibit increased plasma levels of IL-6 but decreased levels of TNFα, whereas sound stress increases IL-6 plasma levels in control rats but not in NLB rats. CONCLUSIONS: Early-life stress induces a persistent elevation of IL-6, hyperalgesia, and susceptibility to chronic muscle pain, which is unveiled by exposure to stress in adults. This probably depends on an interaction between adrenal catecholamines and proinflammatory cytokines acting at muscle nociceptor level.

Innate Stat3-mediated induction of the antimicrobial protein Reg3γ is required for host defense against MRSA pneumonia.

Pulmonary Staphylococcus aureus (SA) infections are a public health concern and a major complication of hyper-IgE syndrome, caused by mutations in STAT3. In contrast to previous findings of skin infection, we observed that clearance of SA from the lung did not require T, B, or NK cells but did require Stat3 activation. Immunohistochemistry showed robust Stat3 phosphorylation in the lung epithelium. We identified that a critical Stat3 target gene in lung epithelium is Reg3g (regenerating islet-derived 3 γ), a gene which is highly expressed in gastrointestinal epithelium but whose role in pulmonary host defense is uncharacterized. Stat3 regulated Reg3g transcription through direct binding at the Reg3g promoter region. Recombinant Reg3γ bound to SA and had both bacteriostatic and bactericidal activity in a dose-dependent fashion. Stat3 inhibition in vivo reduced Reg3g transcripts in the lung, and more importantly, recombinant Reg3γ rescued mice from defective SA clearance. These findings reveal an antibacterial function for lung epithelium through Stat3-mediated induction of Reg3γ.

The interrelationship between bone and fat: from cellular see-saw to endocrine reciprocity.

The number of mature osteoblasts and marrow adipocytes in bone is influenced by the differentiation of the common mesenchymal progenitor cell towards one phenotype and away from the other. Consequently, factors which promote adipogenesis not only lead to fatty marrow but also inhibit osteoblastogenesis, resulting in decreased osteoblast numbers, diminished bone formation and, potentially, inadequate bone mass and osteoporosis. In addition to osteoblast and bone adipocyte numbers being influenced by this skewing of progenitor cell differentiation towards one phenotype, mature osteoblasts and adipocytes secrete factors which may evoke changes in the cell fate and function of each other. This review examines the endogenous factors, such as PPAR-γ2, Wnt, IGF-1, GH, FGF-2, oestrogen, the GP130 signalling cytokines, vitamin D and glucocorticoids, which regulate the selection between osteoblastogenesis and adipogenesis and the interrelationship between fat and bone. The role of adipokines on bone, such as adiponectin and leptin, as well as adipose-derived oestrogen, is reviewed and the role of bone as an energy regulating endocrine organ is discussed.

Dependency of colorectal cancer on a TGF-ß-driven program in stromal cells for metastasis initiation.

A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-ß pathway, yet, paradoxically, they are characterized by elevated TGF-ß production. Here, we unveil a prometastatic program induced by TGF-ß in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-ß on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-ß-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-ß stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.

IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6.

Interleukin-6 (IL-6) is a cytokine with many activities. It has functions in the regulation of the immune system and the nervous system. Furthermore, IL-6 is involved in liver regeneration and in the metabolic control of the body. On target cells, IL-6 binds to an 80 kDa IL-6 receptor (IL-6R). The complex of IL-6 and IL-6R associates with a second protein, gp130, which thereupon dimerizes and initiates intracellular signaling. Whereas gp130 is expressed on all cells, IL-6R is only present on few cells in the body including hepatocytes and some leukocytes. Cells, which do not express IL-6R cannot respond to the cytokine, since gp130 alone has no measurable affinity for IL-6. Interestingly, a soluble form of IL-6R (sIL-6R) comprising the extracellular portion of the receptor can bind IL-6 with a similar affinity as the membrane bound IL-6R. The complex of IL-6 and sIL-6R can bind to gp130 on cells, which do not express the IL-6R, and which are unresponsive to IL-6. This process has been called trans-signaling. Here I will review published evidence that IL-6 trans-signaling is pro-inflammatory whereas classic IL-6 signaling via the membrane bound IL-6R is needed for regenerative or anti-inflammatory activities of the cytokine. Furthermore, the detailed knowledge of IL-6 biology has important consequences for therapeutic strategies aimed at the blockade of the cytokine IL-6.

Interleukin-6--a key regulator of colorectal cancer development.

Growing evidence proposes an important role for pro-inflammatory cytokines during tumor development. Several experimental and clinical studies have linked the pleiotropic cytokine interleukin-6 (IL-6) to the pathogenesis of sporadic and inflammation-associated colorectal cancer (CRC). Increased IL-6 expression has been related to advanced stage of disease and decreased survival in CRC patients. According to experimental studies, these effects are mediated through IL-6 trans-signaling promoting tumor cell proliferation and inhibiting apoptosis through gp130 activation on tumor cells with subsequent signaling through Janus kinases (JAKs) and signal transducer and activator of transcription 3 (STAT3). During recent years, several therapeutics targeting the IL-6/STAT3 pathway have been developed and pose a promising strategy for the treatment of CRC. This review discusses the molecular mechanisms and possible therapeutic targets involved in IL-6 signaling in CRC.

STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation.

Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium. Increased STAT3 pathway activation and TLR2 expression were also associated with poor GC patient survival. Collectively, our data reveal an unexpected role for TLR2 in the oncogenic function of STAT3 that may represent a therapeutic target in GC.