Role of mitogen-activated protein kinase and PI3K pathways in the regulation of IL-12-family cytokines in dendritic cells and the generation of T H-responses
Abstract
Mitogen-activated protein kinases (MAPK) are targets for the immune-modulation of dendritic cells (DC). However, our knowledge of their role in the regulation of IL-12-family cytokines is limited. This study investigated the roles of p38, JNK, p44/42 and PI3K pathways in IL-12/23/27 production by human DC, and their impact on naïve T(H)-responses. We first identified TOP and UBC as robust DC housekeeping genes. Peak transcription of p35 and p40 occurred by 12h, p19 and p28 by 8h and EBI3 by 12-24h. Using selective antagonists, we showed that p38 was a positive regulator of IL-12, 23 and 27, JNK positively regulated IL-12 and IL-27, and inhibition of MEK1/2 had no marked effect. In contrast, the PI3K pathway markedly attenuated IL-23 responses and, to a lesser extent, IL-12, but not IL-27. To identify the role of these soluble factors, we co-stimulated naïve CD4+ T-cells in the presence of DC supernatant. The presence of mature DC supernatant induced not only strong IFNγ responses, but also IL-10 and IL-17A. Inhibition of p38 ablated T(H1), and IL-10 and IL-17A responses, whilst modestly enhancing IL-5 secretion. In contrast, inhibition of MEK1/2 abolished IL-17A production, whilst leaving other responses unaffected, whereas inhibition of JNK or PI3K had no discernable effect. In summary, we describe the expression of IL-12-family cytokines from DC and propose a modified model for their regulation. This study further clarifies the potential for therapeutic modulation through these mediators.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The p38-MAPK pathway is not active in Th2 cells.
“This pathway is not active in Th2 cells (186).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [186]
Cited by
Sorted by citations
Aiello, A., Farzaneh, F., Candore, G., Caruso, C., Davinelli, S., Gambino, C. M., Ligotti, M. E., Zareian, N., & Accardi, G. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02247 · Cited by 693 · see citing works
“This pathway is not active in Th2 cells (186).”
BackgroundThe Mitogen-Activated Protein Kinase (MAPK) Pathway: Role in Immune Evasion by Trypanosomatids
Soares-Silva, M., Diniz, F. F., Gomes, G. N., & Bahia, D. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.00183 · Cited by 233 · see citing works
“The production of IL-12 is regulated by p38 MAPK and, consequently, is involved in the induction of a Th1 response (Jackson et al., 2010; Arthur and Ley, 2013).”
BackgroundHendrickx, W., Simeone, I., Anjum, S., Mokrab, Y., Bertucci, F., Finetti, P., Curigliano, G., Seliger, B., Cerulo, L., Tomei, S., et al. (2017) · OncoImmunology · doi:10.1080/2162402x.2016.1253654 · Cited by 182 · see citing works
“ples, is involved in the induction of IL-12 production, and therefore in the modulation of Th-1 polarization.(85,87,88) Stud-”
BackgroundDáňová, K., Klapetková, A., Kayserová, J., Šedivá, A., Špíšek, R., & Jelinkova, L. P. (2015) · Oncotarget · doi:10.18632/oncotarget.4234 · Cited by 64 · see citing works
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 · see citing works
Arcanjo, N. M. D. O., Andrade, M. J., Padilla, P., Rodríguez, A., Madruga, M. S., & Estévez, M. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.02.023 · Cited by 40 · see citing works
Schaper, K., Kietzmann, M., & Bäumer, W. (2014) · Molecular Immunology · doi:10.1016/j.molimm.2013.11.015 · Cited by 37 · see citing works
Adhikaree, J., Franks, H., Televantos, C., Vaghela, P., Kaur, A. P., Walker, D. A., Schmitz, M., Jackson, A. M., & Patel, P. M. (2019) · OncoImmunology · doi:10.1080/2162402x.2019.1593803 · Cited by 35 · see citing works
Self-citationTerrazas, C. A., Huitron, E., Vázquez-Mendoza, A., Juárez, I., Camacho, G., Calleja, E. A., & Rodríguez‐Sosa, M. (2011) · International Journal of Biological Sciences · doi:10.7150/ijbs.7.1298 · Cited by 32 · see citing works
Mazzola, M. A., Raheja, R., Regev, K., Beynon, V., von Glehn, F., Paul, A., Pierre, I. V., Kivisäkk, P., Weiner, H. L., & Gandhi, R. (2017) · Multiple Sclerosis Journal · doi:10.1177/1352458517740213 · Cited by 33 · see citing works
Impact of HBeAg on the maturation and function of dendritic cells
Lan, S., Wu, L., Wang, X., et al. (2016) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2016.03.024 · Cited by 25 · see citing works
The Ataxia Telangiectasia Mutated Kinase Pathway Regulates IL-23 Expression by Human Dendritic Cells
Wang, Q., Franks, H., Lax, S. J., Refaee, M. E., Malecka, A. A., Shah, S., Spendlove, I., Gough, M. J., Seedhouse, C., Madhusudan, S., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1201484 · Cited by 24 · see citing works
“In this setting, the p38 MAPK is generally accepted to play a positive role in IL12 family cytokine regulation (28).”
BackgroundSelf-citationWang, Q., Franks, H., Porte, J., et al. (2011) · Immunology · doi:10.1111/j.1365-2567.2011.03467.x · Cited by 24 · see citing works
Self-citationMalecka, A. A., Wang, Q., Shah, S., Sutavani, R. V., Spendlove, I., Ramage, J. M., Greensmith, J., Franks, H., Gough, M. J., Saalbach, A., et al. (2016) · Journal of Leukocyte Biology · doi:10.1189/jlb.3a1015-474r · Cited by 25 · see citing works
“12 h after TLR stimulation [35].”
Self-citationBusca, A., Konarski, Y., Gajanayaka, N., O’Hara, S., Angel, J. B., Kozlowski, M., & Kumar, A. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1700199 · Cited by 24 · see citing works
“The adaptive proteins, MyD88 and TIR (Toll/IL-1R) domain–containing adaptor-inducing IFN-b (TRIF), regulate IL-27 p28 and EBI3 transcription following LPS stimulation of murine bone marrow–derived DCs and macrophages (15–17).”
BackgroundInfluentialIL-27 suppresses SKOV3 cells proliferation by enhancing STAT3 and inhibiting the Akt signal pathway
Zhang, Z., Zhou, B., Zhang, K., et al. (2016) · Molecular Immunology · doi:10.1016/j.molimm.2016.09.014 · Cited by 17 · see citing works
Franks, H., Wang, Q., Lax, S. J., et al. (2013) · International Journal of Cancer · doi:10.1002/ijc.28398 · Cited by 16 · see citing works
Self-citationAlvero, A. B., Fox, A. L., Madina, B. R., Krady, M. M., Gogoi, R. P., Chehade, H., Nakaar, V., Almassian, B., Yarovinsky, T. O., Rutherford, T., et al. (2023) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-23-0127 · Cited by 13 · see citing works
Fairman, P., & Angel, J. B. (2012) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2012.04628.x · Cited by 12 · see citing works
Álvarez, C., Amaral, M. M., Langellotti, C. A., et al. (2011) · Immunology · doi:10.1111/j.1365-2567.2011.03478.x · Cited by 11 · see citing works
Cheng, J., Zheng, J., Ma, C., Li, Y., & Hao, H. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.05.010 · Cited by 8 · see citing works
Gajanayaka, N., O’Hara, S., Konarski, Y., Fernandes, J. R., Muthumani, K., Kozlowski, M., Angel, J. B., & Kumar, A. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.4a0716-332rr · Cited by 8 · see citing works
“HIV-1 ssRNA contains sequences that can serve as TLR7 and TLR8 ligands and stimulate production of proinflammatory cytokines by DCs and Mfs [39–41].”
BackgroundInfluentialLangellotti, C. A., Cesar, G. L., Soria, I., et al. (2015) · Vaccine · doi:10.1016/j.vaccine.2015.07.038 · Cited by 8 · see citing works
Upregulation of Interleukin-35 Subunits in Regulatory T Cells in a Murine Model of Allergic Rhinitis
Shen, H., Wang, C., Fan, E., et al. (2014) · ORL · doi:10.1159/000369141 · Cited by 7 · see citing works
(2021) · Frontiers research topics · doi:10.3389/978-2-88966-718-5 · Cited by 3 · see citing works
LILRA3 is related to monocyte-derived dendritic cell maturation and activation.
Wu, X., Cheng, Q., Jiang, H., et al. (2021) · PubMed · doi:10.22038/ijbms.2020.50714.11555 · Cited by 1 · see citing works
“Dendritic cell maturation requires various signaling pathways, like the mitogen-activated protein kinase (MAPK) pathway, JAK/STAT1 pathway, and the PI3K/ AKT signaling pathway(24-26).”
BackgroundGajanayaka, N. (2015) · uO Research (University of Ottawa) · doi:10.20381/ruor-3938
“LPS/IFNγ-induced IL-27 production was; however, regulated by the JNK MAPK in myeloid DCs (284).”
InfluentialThe Immunopathology of Behçet’s Disease
Suzuki, N., & Shimizu, J. (2014) · Springer eBooks · doi:10.1007/978-4-431-54487-6_2
Regulation of IL-12, IL-23, IL-27 in Response to IFN-γ/LPS in Human Monocytes and Macrophages
Blahoianu, M. A. (2013) · uO Research (University of Ottawa) · doi:10.20381/ruor-3302
Kinner, L. B. (2017) · D-Scholarship@Pitt (University of Pittsburgh)
O’Hara, S. (2012) · uO Research (University of Ottawa) · doi:10.20381/ruor-5966
“regulation of LPS/IFN-induced IL-27 production in myeloid DCs (265).”
BackgroundInfluential
- Authors
- Jackson
- Venue
- PubMed
- Publisher
- National Institutes of Health
- Published
- 2010-12-01
- Volume
- 21
- Issue
- 4
- Pages
- 319-28
- OpenAlex
- W1908109923
- Cited by
- 31
- References
- 0
- Citations by year
- 2025: 1 · 2023: 1 · 2021: 2 · 2019: 3 · 2018: 1 · 2017: 5 · 2016: 4 · 2015: 3 · 2014: 3 · 2013: 3 · 2012: 2
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- PubMed (publishedVersion)
- PubMed
- Funders
- National Institute for Health and Care Research (ACF-2007-12-008)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- mitogen-activated protein kinase, PI3K signaling, IL-12 family cytokines, IL-12, IL-23, IL-27, dendritic cells, p38 MAPK, JNK, MEK1/2, T helper cell differentiation, Th1 response, IL-17A, IL-10, IL-5, interferon-gamma, cytokine gene expression, housekeeping genes
- MeSH terms
- Cells, Cultured, Dendritic Cells, Enzyme Activation, Gene Expression Regulation, T-Lymphocytes, Helper-Inducer, Humans, Interleukins, Signal Transduction, Interleukin-12, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinases, Protein Kinase Inhibitors, Interleukin-23
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
