Tumor Progression Locus 2 (Map3k8) Is Critical for Host Defense against Listeria monocytogenes and IL-1β Production

Mielke, Lisa A; Elkins, Karen L; Wei, Lai; Starr, Robyn; Tsichlis, Philip N; O'Shea, John J; Watford, Wendy T

doi:10.4049/jimmunol.0901336

Cited by 101Immune Response and InflammationImmune responses and vaccinationsInflammasome and immune disorders

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Tumor Progression Locus 2 (Map3k8) Is Critical for Host Defense against Listeria monocytogenes and IL-1β Production

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Mielke, Lisa A, Elkins, Karen L, Wei, Lai, Starr, Robyn, Tsichlis, Philip N, O'Shea, John J, Watford, Wendy T·2009·The Journal of Immunology

DOI 10.4049/jimmunol.0901336PMC PMC2946069

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Abstract

Tumor progression locus 2 (Tpl2, also known as Map3k8 and Cot) is a serine-threonine kinase critical in innate immunity, linking toll-like receptors (TLRs) to TNF production through its activation of ERK. Tpl2−/− macrophages have abrogated TNF production but overproduce IL-12 in response to TLR ligands. Despite enhanced IL-12 production, Tpl2−/− T cells have impaired IFN-γ production. Therefore, the role of Tpl2 in a bona fide bacterial infection where all of these cytokines are important in host defense is unclear. To address this issue, we infected Tpl2−/− mice with the model pathogen Listeria monocytogenes. We found that Tpl2−/− mice infected i.v. with L. monocytogenes had increased pathogen burdens compared with wild-type mice and rapidly succumbed to infection. Enhanced susceptibility correlated with impaired signaling through TLR2 and nucleotide-binding oligomerization domain 2, two receptors previously shown to mediate Listeria recognition. Surprisingly, TNF production in response to infection was not significantly impaired, even though Tpl2 has been implicated in the regulation of TNF. We found that the role of Tpl2 has cell-type specific effects in regulating TNF and transduces signals from some, but not all, pattern recognition receptors (PRR). In contrast to the cell-type- and receptor-specific regulation of TNF, we found that Tpl2 is essential for IL-1β production from both macrophages and dendritic cells. These studies implicate Tpl2 as an important mediator for collaboration of pattern recognition receptors with danger-associated molecular patterns to induce TNF and IL-1β production and optimal host defense.

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Map3k7 and Map3k8 are essential for macrophage bacterial killing.
“Map3k7 and Map3k8 genes were highly upregulated and were essential for macrophage bacterial killing [47,48], respectively.”
From Trained Immunity Provides Long-Term Protection against Bacterial Infections in Channel Catfish (2022) · cites this paper as [48]
The Results section, “Tpl2 controls IL-1β production in response to L. monocytogenes” (page unavailable), reports no significant difference in bacterial uptake or growth within wild-type and Map3k8/Tpl2-deficient macrophages. It concludes that the greater bacterial burden in deficient mice was not due to bacterial survival within macrophages. The source therefore does not support the claim that Map3k8 is essential for macrophage bacterial killing; the separate Map3k7 attribution is not assessed here. (LLM, conf=0.90)
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Xu, D., Matsumoto, M. L., McKenzie, B. S., & Zarrin, A. A. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.11.031 · Cited by 78
IL-12 selectively programs effector pathways that are stably expressed in human CD8+ effector memory T cells in vivo
Chowdhury, F. Z., Ramos, H. J., Davis, L. S., Forman, J., & Farrar, J. D. (2011) · Blood · doi:10.1182/blood-2011-05-357111 · Cited by 69
MAP Kinase Signaling at the Crossroads of Inflammasome Activation
Vervaeke, A., & Lamkanfi, M. (2025) · Immunological Reviews · doi:10.1111/imr.13436 · Cited by 68
Coordinate Regulation of TPL-2 and NF-κB Signaling in Macrophages by NF-κB1 p105
Yang, H., Papoutsopoulou, S., Belich, M. P., Brender, C., Janzen, J., Gantke, T., Handley, M., & Ley, S. C. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00564-12 · Cited by 67
TLR and TNF-R1 activation of the MKK3/MKK6–p38α axis in macrophages is mediated by TPL-2 kinase
Pattison, M. J., Mitchell, O., Flynn, H. R., Chen, C.-S., Yang, H., Ben-Addi, H., Boeing, S., Snijders, A. P., & Ley, S. C. (2016) · Biochemical Journal · doi:10.1042/bcj20160502 · Cited by 61
The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation
Senger, K., Pham, V. C., Varfolomeev, E. E., Hackney, J. A., Corzo, C. A., Collier, J. L., Lau, V. W. C., Huang, Z., Hamidzadeh, K., Caplazi, P., et al. (2017) · Science Signaling · doi:10.1126/scisignal.aah4273 · Cited by 59
The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy
Bedognetti, D., Roelands, J. P., Decock, J. V., Wang, E., & Hendrickx, W. (2017) · Emerging Topics in Life Sciences · doi:10.1042/etls20170142 · Cited by 59
Macrophages in multiple myeloma: emerging concepts and therapeutic implications
Asimakopoulos, F. A., Kim, J., Denu, R. A., Hope, C. L., Jensen, J. L., Ollar, S. J., Hebron, E., Flanagan, C. E., Callander, N. S., & Hematti, P. (2013) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2013.778409 · Cited by 51
Cross Talk between Inhibitory Immunoreceptor Tyrosine-Based Activation Motif-Signaling and Toll-Like Receptor Pathways in Macrophages and Dendritic Cells
Hirsch, I., Janovec, V., Stránská, R., & Bendriss‐Vermare, N. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00394 · Cited by 50
Sterile Inflammation in Acetaminophen-induced Liver Injury Is Mediated by Cot/tpl2
Sanz‐García, C., Ferrer‐Mayorga, G., González‐Rodríguez, Á., Valverde, Á. M., Martín‐Duce, A., Velasco-Martin, J. P., Regadera, J., Fernández, M., & Alemany, S. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.439547 · Cited by 49
Biomarker-based classification of bacterial and fungal whole-blood infections in a genome-wide expression study
Dix, A., nniger, K. H. ⁄., Weber, M., Guthke, R., Kurzai, O., & Linde, J. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.00171 · Cited by 46
IκB Kinase 2 Regulates TPL-2 Activation of Extracellular Signal-Regulated Kinases 1 and 2 by Direct Phosphorylation of TPL-2 Serine 400
Roget, K., Ben-Addi, A., Mambole, A., Gantke, T., Yang, H.-T., Janzen, J., MORRICE, N. A., Abbott, D. W., & Ley, S. C. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.01065-12 · Cited by 46
Tumor progression locus 2/Cot is required for activation of extracellular regulated kinase in liver injury and toll-like receptor–induced TIMP-1 gene transcription in hepatic stellate cells in mice
Perugorria, M. J., Murphy, L. B., Fullard, N., Chakraborty, J. B., Vyrla, D., Wilson, C. L., Oakley, F., Mann, J., & Mann, D. A. (2012) · Hepatology · doi:10.1002/hep.26108 · Cited by 42
Cot/tpl2-MKK1/2-Erk1/2 controls mTORC1-mediated mRNA translation in Toll-like receptor–activated macrophages
López‐Peláez, M., Fumagalli, S., Sanz‐García, C., Herrero, C., Guerra, S., Fernández, M., & Alemany, S. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-02-0135 · Cited by 42
Tumor Progression Locus 2 (Tpl2) Kinase as a Novel Therapeutic Target for Cancer: Double-Sided Effects of Tpl2 on Cancer
Lee, H. J., Choi, H. Y., Joo, K. M., & Nam, D. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms16034471 · Cited by 40
IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and -2 MAP kinases
Ben-Addi, A., Mambole, A., Brender, C., Martin, S. R., Janzen, J., Kjaer, S., Smerdon, S. J., & Ley, S. C. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1320440111 · Cited by 39
Cystatin cures visceral leishmaniasis by NF‐κB‐mediated proinflammatory response through co‐ordination of TLR/MyD88 signaling with p105‐Tpl2‐ERK pathway
Kar, S., Ukil, A., & Das, P. K. (2010) · European Journal of Immunology · doi:10.1002/eji.201040533 · Cited by 39
Listeria monocytogenes and the Inflammasome: From Cytosolic Bacteriolysis to Tumor Immunotherapy
Theisen, E., & Sauer, J. (2016) · Current topics in microbiology and immunology · doi:10.1007/978-3-319-41171-2_7 · Cited by 38
Regulation of Experimental Autoimmune Encephalomyelitis by TPL-2 Kinase
Sriskantharajah, S., Gückel, E., Tsakiri, N., Kierdorf, K., Brender, C., Ben-Addi, A., Veldhoen, M., Tsichlis, P. N., Stockinger, B., O’Garra, A., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1300172 · Cited by 37
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Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor α via MAP3K8
Paardekooper, L. M., Bendix, M. B., Ottria, A., de Haer, L. W., ter Beest, M., Radstake, T. R. D. J., Marut, W., & van den Bogaart, G. (2018) · Bioscience Reports · doi:10.1042/bsr20182019 · Cited by 37
Identification and Classification of Differentially Expressed Genes and Network Meta-Analysis Reveals Potential Molecular Signatures Associated With Tuberculosis
Alam, A., Imam, N., Ahmed, M. M., Tazyeen, S., Tamkeen, N., Farooqui, A., Malik, M. Z., & Ishrat, R. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00932 · Cited by 36
TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations
Dodhiawala, P. B., Khurana, N., Zhang, D., Cheng, Y., Li, L., Wei, Q., Seehra, K., Jiang, H., Grierson, P. M., Wang‐Gillam, A., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137660 · Cited by 34
Tpl2 Inhibitors Thwart Endothelial Cell Function in Angiogenesis and Peritoneal Dissemination
Lee, W., Lan, K., Chou, C., Yi, Y., Chen, W.-C., Pan, H.-C., Peng, Y., Wang, K.-B., Chen, Y.-C., Chao, T., et al. (2013) · Neoplasia · doi:10.1593/neo.121914 · Cited by 30
Genetic and pharmacological targeting of TPL-2 kinase ameliorates experimental colitis: a potential target for the treatment of Crohn's disease?
Lawrenz, M. B., Visekruna, A., Kühl, A. A., Schmidt, N., Kaufmann, S. H. E., & Steinhoff, U. (2011) · Mucosal Immunology · doi:10.1038/mi.2011.57 · Cited by 30
Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity
Njunge, L. W., Estania, A. P., Guo, Y., Liu, W., & Yang, L. (2020) · Theranostics · doi:10.7150/thno.45848 · Cited by 29
Cot/tpl2 (MAP3K8) Mediates Myeloperoxidase Activity and Hypernociception following Peripheral Inflammation*
Soria‐Castro, I., Krzyzanowska, A., López‐Peláez, M., Regadera, J., Ferrer, G., Montoliu, L., Rodríguez-Ramos, R., Fernández, M., & Alemany, S. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.169409 · Cited by 29
Oncogenic KRAS-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities
Bansod, S., Dodhiawala, P. B., & Lim, K. (2021) · Cancers · doi:10.3390/cancers13215481 · Cited by 28
Mitogen-activated Protein Kinase-mediated Licensing of Interferon Regulatory Factor 3/7 Reinforces the Cell Response to Virus
Schmid, S., Sachs, D. M., & tenOever, B. R. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.519934 · Cited by 28
Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer
Khurana, N., Dodhiawala, P. B., Bulle, A. S., & Lim, K. (2020) · Cancers · doi:10.3390/cancers12092675 · Cited by 27
Tumor Progression Locus 2 (Tpl2) Kinase Promotes Chemokine Receptor Expression and Macrophage Migration during Acute Inflammation
Rowley, S. M., Kuriakose, T., Dockery, L. M., Tran-Ngyuen, T., Gingerich, A. D., Wei, L., & Watford, W. T. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.559344 · Cited by 27
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Implication of the Tpl2 Kinase in Inflammatory Changes and Insulin Resistance Induced by the Interaction Between Adipocytes and Macrophages
Ceppo, F., Berthou, F., Jager, J., Dumas, K., Cormont, M., & Tanti, J. (2014) · Endocrinology · doi:10.1210/en.2013-1815 · Cited by 26
Differential regulation of lipopolysaccharide-induced IL-1β and TNF-α production in macrophages by palmitate via modulating TLR4 downstream signaling
Fang, C., Wang, L., Qiao, J., Chang, L., He, Q., Zhang, X., & Liu, M. R. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.108456 · Cited by 25
Transcriptomic analysis of immune response to bacterial lipopolysaccharide in zebra finch (Taeniopygia guttata)
Scalf, C., Chariker, J. H., Rouchka, E. C., & Ashley, N. T. (2019) · BMC Genomics · doi:10.1186/s12864-019-6016-3 · Cited by 25
Tumor Progression Locus 2-dependent Oxidative Burst Drives Phosphorylation of Extracellular Signal-regulated Kinase during TLR3 and 9 Signaling
Kuriakose, T., Rada, B., & Watford, W. T. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.587121 · Cited by 23
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An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility
Matzaraki, V., Gresnigt, M. S., Jaeger, M., Ricaño-Ponce, I., Johnson, M. D., Oosting, M., Franke, L., Withoff, S., Perfect, J. R., Joosten, L. A. B., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0180824 · Cited by 23
Tumor Progression Locus 2 Promotes Induction of IFNλ, Interferon Stimulated Genes and Antigen-Specific CD8+ T Cell Responses and Protects against Influenza Virus
Kuriakose, T., Tripp, R. A., & Watford, W. T. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1005038 · Cited by 22
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Tumor Progression Locus 2 (Tpl2) Activates the Mammalian Target of Rapamycin (mTOR) Pathway, Inhibits Forkhead Box P3 (FoxP3) Expression, and Limits Regulatory T Cell (Treg) Immunosuppressive Functions
Li, X., Acuff, N. V., Peeks, A., Kirkland, R. A., Wyatt, K. D., Nagy, T., & Watford, W. T. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.718783 · Cited by 22
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TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology
Kannan, Y., Perez-Lloret, J., Li, Y., Entwistle, L. J., Khoury, H., Papoutsopoulou, S., Mahmood, R., Mansour, N. R., Huang, S. C., Pearce, E. J., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005783 · Cited by 22
Foot-and-Mouth Disease Virus Structural Protein VP1 Destroys the Stability of the TPL2 Trimer by Degradation of TPL2 To Evade Host Antiviral Immunity
Zhang, K., Yan, M., Hao, J., Shen, C., Zhu, Z., Zhang, D., Hou, J., Xu, G., Li, D., Zheng, H., et al. (2020) · Journal of Virology · doi:10.1128/jvi.02149-20 · Cited by 22
Genome-wide association study of disease resilience traits from a natural polymicrobial disease challenge model in pigs identifies the importance of the major histocompatibility complex region
Cheng, J., Fernando, R. L., Cheng, H., Kachman, S. D., Lim, K., Harding, J. C. S., Dyck, M. K., Fortin, F., Plastow, G. S., Canada, P., et al. (2021) · G3 Genes Genomes Genetics · doi:10.1093/g3journal/jkab441 · Cited by 22
Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors
Glatthar, R., Stojanovic, A., Troxler, T. J., Mattes, H., Möbitz, H., Beerli, R., Blanz, J., Gassmann, E., Drückes, P., Fendrich, G., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00598 · Cited by 21
MAP3K8 (TPL2/COT) Affects Obesity-Induced Adipose Tissue Inflammation without Systemic Effects in Humans and in Mice
Ballak, D. B., van Essen, P., van Diepen, J. A., Jansen, H., Hijmans, A., Matsuguchi, T., Sparrer, H., Tack, C. J., Netea, M. G., Joosten, L. A. B., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089615 · Cited by 20
Trained Immunity Provides Long-Term Protection against Bacterial Infections in Channel Catfish
Petrie-Hanson, L., & Peterman, A. E. (. (2022) · Pathogens · doi:10.3390/pathogens11101140 · Cited by 19
Tpl2 promotes neutrophil trafficking, oxidative burst, and bacterial killing
Acuff, N. V., Li, X., Elmore, J. P., Rada, B., & Watford, W. T. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.3a0316-146r · Cited by 19
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Secoeudesma sesquiterpenes lactone A alleviates inflammation and offers adjuvant protection in severe infection of carbapenem-resistant Klebsiella pneumoniae
Jiang, X., Chen, Y., Liu, D., Shi, T., Cheng, X., He, W., Li, Y., Ryffel, B., Zheng, S. G., & Zheng, Y. (2020) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2020.112605 · Cited by 18
Severe Dermatitis Associated with Spontaneous Staphylococcus xylosus Infection in Rag-/-Tpl2-/- Mice.
Acuff, N. V., LaGatta, M., Nagy, T., & Watford, W. T. (2017) · PubMed Central · Cited by 17
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Map3k8 controls granulocyte colony-stimulating factor production and neutrophil precursor proliferation in lipopolysaccharide-induced emergency granulopoiesis
Sánchez, Á., Relaño‐Rupérez, C., Carrasco, A., Contreras‐Jurado, C., Martín‐Duce, A., Aranda, A., & Alemany, S. (2017) · Scientific Reports · doi:10.1038/s41598-017-04538-3 · Cited by 15
Tumor progression locus 2 reduces severe allergic airway inflammation by inhibiting Ccl24 production in dendritic cells
Kannan, Y., Li, Y., Coomes, S. M., Okoye, I., Pelly, V. S., Sriskantharajah, S., Gückel, E., Webb, L. M., Czieso, S., Nikolov, N., et al. (2016) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2016.05.031 · Cited by 14
miR‑148 family members are putative biomarkers for sepsis
Dong, L., Li, H., Zhang, S., & Yang, G. (2019) · Molecular Medicine Reports · doi:10.3892/mmr.2019.10174 · Cited by 14
Bioinformatics-Based Analysis of the lncRNA-miRNA-mRNA Network and TF Regulatory Network to Explore the Regulation Mechanism in Spinal Cord Ischemia/Reperfusion Injury
Wang, D., Wang, L., Han, J., Zhang, Z.-L., Fang, B., & Chen, F. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.650180 · Cited by 14
The Tpl2 Kinase Regulates the COX-2/Prostaglandin E2 Axis in Adipocytes in Inflammatory Conditions
Berthou, F., Ceppo, F., Dumas, K., Massa, F., Vergoni, B., Alemany, S., Cormont, M., & Tanti, J. (2015) · Molecular Endocrinology · doi:10.1210/me.2015-1027 · Cited by 13
TPL-2 Inhibits IFN-β Expression via an ERK1/2-TCF-FOS Axis in TLR4-Stimulated Macrophages
Blair, L., Pattison, M. J., Chakravarty, P., Papoutsopoulou, S., Bakiri, L., Wagner, E. F., Smale, S. T., & Ley, S. C. (2022) · The Journal of Immunology · doi:10.4049/jimmunol.2100213 · Cited by 13
Cot/tpl2 participates in the activation of macrophages by adiponectin
Sanz‐García, C., Nagy, L. E., Lasunción, M. A., Fernández, M., & Alemany, S. (2014) · Journal of Leukocyte Biology · doi:10.1189/jlb.0913486 · Cited by 13
Tumor Progression Locus 2 Differentially Regulates IFNγ and IL-17 Production by Effector CD4+ T Cells in a T Cell Transfer Model of Colitis
Acuff, N. V., Li, X., Kirkland, R. A., Nagy, T., & Watford, W. T. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119885 · Cited by 11
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A molluscan extracellular signal-regulated kinase is involved in host response to immune challenges in vivo and in vitro
Qu, F., Xiang, Z., Li, ., Xiao, S., Mao, F., Qin, Y., Zhou, Y., Ma, H., & Yu, Z. (2017) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2017.01.038 · Cited by 11
TPL2 Is a Key Regulator of Intestinal Inflammation in Clostridium difficile Infection
Wang, Y., Wang, S., Kelly, C. P., Feng, H., Greenberg, A. S., & Sun, X. (2018) · Infection and Immunity · doi:10.1128/iai.00095-18 · Cited by 11
Tpl2 Ablation Leads to Hypercytokinemia and Excessive Cellular Infiltration to the Lungs During Late Stages of Influenza Infection
Latha, K., Jamison, K. F., & Watford, W. T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.738490 · Cited by 9
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Listr1 locus regulates innate immunity against Listeria monocytogenes infection in the mouse liver possibly through Cxcl11 polymorphism
Qi, Z., Wang, J., Han, X., Yang, J., Zhao, G., & Cao, Y. (2014) · Immunogenetics · doi:10.1007/s00251-014-0761-x · Cited by 9
TPL-2 restricts Ccl24-dependent immunity to Heligmosomoides polygyrus
Kannan, Y., Entwistle, L. J., Pelly, V. S., Perez-Lloret, J., Walker, A. W., Ley, S. C., & Wilson, M. S. (2017) · PLoS Pathogens · doi:10.1371/journal.ppat.1006536 · Cited by 9
The combination of TPL2 knockdown and TNFα causes synthetic lethality via caspase-8 activation in human carcinoma cell lines
Serebrennikova, O. B., Paraskevopoulou, M. D., Aguado-Fraile, E., Taraslia, V., Ren, W., Thapa, G., Roper, J., Du, K., Croce, C. M., & Tsichlis, P. N. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1901465116 · Cited by 9
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Foot-and-Mouth Disease Virus Capsid Protein VP1 Antagonizes TPL2-Mediated Activation of the IRF3/IFN-β Signaling Pathway to Facilitate the Virus Replication
Hao, J., Shen, C., Wei, N., Yan, M., Zhang, X., Xu, G., Zhang, D., Hou, J., Cao, W., Ye, J., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.580334 · Cited by 8
The TRIM4 E3 ubiquitin ligase degrades TPL2 and is modulated by oncogenic KRAS
Bansod, S., Dodhiawala, P. B., Geng, Y., Bulle, A. S., Liu, P., Li, L., Townsend, R., Grierson, P. M., Held, J. M., Adhikari, H., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114667 · Cited by 7
Genetic and pharmacologic inhibition of Tpl2 kinase is protective in a mouse model of ventilator-induced lung injury
Kaniaris, E., Vaporidi, K., Vergadi, E., Theodorakis, E. E., Kondili, Ε., Lagoudaki, E. D., Tsatsanis, C., & Georgopoulos, D. (2014) · Intensive Care Medicine Experimental · doi:10.1186/2197-425x-2-15 · Cited by 7
Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination
Acuff, N. V., Li, X., Latha, K., Nagy, T., & Watford, W. T. (2017) · Infection and Immunity · doi:10.1128/iai.00193-17 · Cited by 7
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Teleost-specific TLR23 in Takifugu rubripes recruits MyD88 to trigger ERK pathway and promotes antibacterial defense
Du, Y.-T., Zhang, H., Li, Y., Li, X.-P., Yuan, Z., & Li, M.-F. (2024) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2024.109724 · Cited by 6
Influenza-induced Tpl2 expression within alveolar epithelial cells is dispensable for host viral control and anti-viral immunity
Wyatt, K. D., Sarr, D., Sakamoto, K., & Watford, W. T. (2022) · PLoS ONE · doi:10.1371/journal.pone.0262832 · Cited by 5
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The Influenza-Induced Pulmonary Inflammatory Exudate in Susceptible Tpl2-Deficient Mice Is Dictated by Type I IFN Signaling
Latha, K., Patel, Y., Rao, S., & Watford, W. T. (2022) · Inflammation · doi:10.1007/s10753-022-01736-8 · Cited by 5
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MicroRNA-370-5p inhibits pigmentation and cell proliferation by downregulating mitogen-activated protein kinase kinase kinase 8 expression in sheep melanocytes
Ji, K., Ru-jun, W., Zheng-zhou, W. A. N. G., Tian, Q., Zhang, W., & Zhang, Y. (2023) · Journal of Integrative Agriculture · doi:10.1016/j.jia.2023.02.018 · Cited by 5
Characterization of the impact of dietary immunostimulant CpG on the expression of mRNA biomarkers involved in the immune responses in Atlantic salmon (Salmo salar)
Xue, X., Eslamloo, K., Caballero‐Solares, A., Katan, T., Umasuthan, N., Taylor, R. G., Fast, M. D., Andreassen, R., & Rise, M. L. (2024) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2024.109840 · Cited by 4
The Role of Tpl2 Protein Kinase in Carcinogenesis and Inflammation
DeCicco-Skinner, K., Deshpande, M. M., & Wiest, J. S. (2012) · InTech eBooks · doi:10.5772/38135 · Cited by 4
Deletion of tumor progression locus 2 attenuates alcohol-induced hepatic inflammation.
Stice, C. P., Hussain, S., Liu, C., Ausman, L. M., Wang, X., & Greenberg, A. S. (2016) · PubMed Central · doi:10.3978/j.issn.2304-3881.2015.12.11 · Cited by 3
Tumor Progression Locus 2 Protects against Acute Respiratory Distress Syndrome in Influenza A Virus-Infected Mice
Latha, K., Rao, S., Sakamoto, K., & Watford, W. T. (2022) · Microbiology Spectrum · doi:10.1128/spectrum.01136-22 · Cited by 2
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Molecular Pathogenesis and Immune Evasion of Vesicular Stomatitis New Jersey Virus Inferred from Genes Expression Changes in Infected Porcine Macrophages
Velázquez-Salinas, L., Canter, J. A., Zhu, J. J., & Rodrı́guez, L. L. (2021) · Pathogens · doi:10.3390/pathogens10091134 · Cited by 2
Stage specific classification of DEGs via statistical profiling and network analysis reveals potential biomarker associated with various stages of TBPreprint
Ishrat, R. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/414110 · Cited by 2
TPL2 kinase activity is required for Il1b transcription during LPS priming but dispensable for NLRP3 inflammasome activation
Fahey, D. L., Patel, N., & Watford, W. T. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1496613 · Cited by 1
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Brucella proline racemase protein A targets Tpl2 to promote IL-10 secretion for establishment of chronic infection
Zhang, H., Wang, Y., Wang, Y., Hou, H., Wang, Y., Deng, X., Xu, Z., Xia, X., Xu, M., Wang, Z., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1808256 · Cited by 1
TPL2
Virla, D., Tsatsanis, C., & Eliopoulos, A. G. (2016) · Springer eBooks · doi:10.1007/978-1-4614-6438-9_626-1 · Cited by 1
REGULATION OF INFLAMMATION, LUNG INJURY AND AUTOPHAGY DURING PSEUDOMONAS AERUGINOSA LUNG INFECTION
Junkins, R. D. (2016) · DalSpace (Dalhousie University)
Transcriptomic Response to Immune Challenge in Zebra Finch (Taeniopygia Guttata) Using RNA-SEQ
Scalf, C. (2018) · TopSCHOLAR (Western Kentucky University)
Rôle de la kinase inflammatoire Tpl2 dans l'inflammation du tissu adipeux lors de l'obésité
Ceppo, F. (2014) · theses.fr (ABES) · doi:10.70675/4f725590z4b0az43c5zad51z96dea7639de8
Role of the serine-threonine kinase tpl2 in regulatory T cell development and function
Li, X. (2016)
TPL2
Virla, D., Tsatsanis, C., & Eliopoulos, A. G. (2017) · Springer eBooks · doi:10.1007/978-3-319-67199-4_626
TPL-2 regulates inflammation in ulcerative colitis through activating JNK/ERK pathwayPreprint
Cui, X. T., Dong, N.-N., Zhao, C., & Ji, C. (2023) · Research Square · doi:10.21203/rs.3.rs-2401264/v1
Identification de nouvelles stratégies thérapeutiques renforçant le rôle des analogues du GLP-1 pour préserver et/ou restaurer la masse fonctionnelle β pancréatique
Varin, E. M. (2013) · theses.fr (ABES) · doi:10.70675/24645bb4zf084z43e7za08czc692f9d0eba1
Impairment of type I interferon production in plasmacytoid dendritic cells : targeting the BCR-like signaling pathway
Aouar, B. (2015) · theses.fr (ABES) · doi:10.70675/62995d41zd54fz4698za6afz7415be2f7a57
Rôle de la protéine de matrice du virus de la rage dans la régulation des voies NF-κB et des MAPKs
Besson, B. (2016) · theses.fr (ABES) · doi:10.70675/fc47094dzaaa8z4ad5zb572zafb266698855
Coopération de la phosphoprotéine et de la protéine de matrice du virus de la rage dans la modulation des voies de signalisation Jak/Stat et NF-!B et développement d’une approche thérapeutique
Sonthonnax, F. (2017) · theses.fr (ABES) · doi:10.70675/93be8d4dzc4b9z4f85za9c0z8bfbda61e63a
Single-Cell RNA-Sequencing Data Analysis and Identification of Potential Genes Associated with Pathogenesis and Prognosis of IgA NephropathyPreprint
Vastrad, B. M., Pattanashetti, S., Patil, S., & Vastrad, C. M. (2026) · Research Square · doi:10.21203/rs.3.rs-10057610/v1
BindingDB Entry 50047823: Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors.
BindingDB (2018) · UC San Diego · doi:10.7270/q29p33mr

Toll-Like Receptor 2 Is Required for Optimal Control of Listeria monocytogenes Infection
Torres, D., Barrier, M., Bihl, F., Quesniaux, V. J. F., Maillet, I., Akira, S., Ryffel, B., & Erard, F. (2004) · Infection and Immunity · doi:10.1128/iai.72.4.2131-2139.2004 · Cited by 191
TLR2 Regulates Mast Cell IL-6 and IL-13 Production During Listeria monocytogenes Infection
Soria-Castro, R., Alfaro-Doblado, Á. R., Rodríguez-López, G. M., Campillo-Navarro, M., Meneses-Preza, Y. G., Galán-Salinas, A., Álvarez-Jiménez, V. D., Yam‐Puc, J. C., Munguía-Fuentes, R., Domínguez-Flores, A., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.650779 · Cited by 17
Mitogen-Activated Protein Kinase-Activated Protein Kinase 2-Deficient Mice Show Increased Susceptibility to Listeria monocytogenes Infection
Lehner, M. D., Schwoebel, F., Kotlyarov, A., Leist, M., Gaestel, M., & Härtung, T. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.9.4667 · Cited by 82
Implications of Toll-like receptor (TLR) and membrane TNF during infection by Listeria monocytogenes
Torres, D., & Erard, F. (2005) · OpenGrey (Institut de l'Information Scientifique et Technique)
Implications des récepteurs Toll-like et du TNF membranaire dans la réponse immunitaire contre Listeria monocytogenes
Torres, D. (2005)

Authors: Mielke, L. A., Elkins, K. L., Wei, L., Starr, R., Tsichlis, P. N., O'Shea, J. J., & Watford, W. T.
Affiliations: National Institutes of Health (US)
Center for Biologics Evaluation and Research (US)
St Vincents Institute of Medical Research (AU)
Tufts Medical Center (US)
Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health Bethesda , MD 20892
Corresponding author: Wei, Lai
ORCID: Mielke, Lisa A
Elkins, Karen L
Wei, Lai
Tsichlis, Philip N
Watford, Wendy T
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 2009-12
Volume: 183
Issue: 12
Pages: 7984-7993
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.0901336
PMC: PMC2946069
OpenAlex: W2130201289
Cited by: 98
References: 62
Citations by year: 2026: 2 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 5 · 2021: 8 · 2020: 6 · 2019: 4 · 2018: 4 · 2017: 13 · 2016: 11 · 2015: 5 · 2014: 12 · 2013: 7 · 2012: 8
FWCI: 2.01
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
Office of Science
National Cancer Institute (R01CA095431)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (#1 K22 AR53953-01, Z01AR041132, ZIAAR041161, Z01AR041159, K22AR053953, Z01AR041160, ZIAAR041167, ZIAAR041106, Z01AR041106, Z01AR041167, ZIAAR041159)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords: TPL2, MAP3K8, Listeria monocytogenes, IL-1β, TNF production, TLR2, NOD2, pattern recognition receptors, innate immunity, macrophages, dendritic cells, interferon-gamma, bacterial infection susceptibility, damage-associated molecular patterns
MeSH terms: Animals, Cells, Cultured, Female, Gene Expression Regulation, Immunity, Innate, Listeriosis, Listeria monocytogenes, Male, Mice, Inbred C57BL, Proto-Oncogene Proteins, Transduction, Genetic, Signal Transduction, Mice, Knockout, MAP Kinase Kinase Kinases, Mice, Interleukin-1beta

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Tumor Progression Locus 2 (Map3k8) Is Critical for Host Defense against Listeria monocytogenes and IL-1β Production

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