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IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells
Open accessAbstract
We found IL-6-STAT3 pathway suppresses MHC class II (MHCII) expression on dendritic cells (DCs) and attenuates T cell activation. Here, we showed that IL-6-STAT3 signaling reduced intracellular MHCII alphabeta dimmer, Ii, and H2-DM levels in DCs. IL-6-mediated STAT3 activation decreased cystatin C level, an endogenous inhibitor of cathepsins, and enhanced cathepsin activities. Importantly, cathepsin S inhibitors blocked reduction of MHCII alphabeta dimer, Ii, and H2-DM in the IL-6-treated DCs. Overexpression of cystatin C suppressed IL-6-STAT3-mediated increase of cathepsin S activity and reduction of MHCII alphabeta dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII alphabeta dimer, Ii, and H2-DM levels, LPS-mediated surface expression of MHCII and suppressed CD4(+) T cell activation. IL-6-gp130-STAT3 signaling in vivo decreased cystatin C expression and MHCII alphabeta dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII alphabeta dimer, Ii, and H2-DM levels in DCs, and suppresses CD4(+) T cell-mediated immune responses.
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“CyC is a known potent inhibitor of cysteine proteases,74 such as those involved in antigen presentation,75”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [75]
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“Indeed, cathepsin S expression can be activated in dendritic cells by IL-6 in a STAT-3-dependent process [57], while the human MMP-12 promoter has a STAT binding sequence [55].”
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Novel biomarkers indicating repair or progression after acute kidney injury
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“77 78-81 In addition, we have unveiled that polyamines act as the key downstream effector of VISTA and causally steer myeloid differentiation; blocking polyamine production in WT monocytic progenitors curbed MDSC differentiation and induced moDC expansion, while supplementing putrescine in Vsir −/−…”
BackgroundOkuneva, O., Körber, I., Li, Z., Tian, L., Joensuu, T. H., Kopra, O., & Lehesjoki, A. (2014) · Glia · doi:10.1002/glia.22760 · Cited by 49
“The reduced surface expression of MHCII in Cstb2/ 2 microglia may thus be mediated by increased cathepsin activity, which has been demonstrated in cultured Cstb2/2 mouse cerebellar granule neurons (Lehtinen et al., 2009) and also in lympho- blastoid cells of EPM1 patients (Rinne et al., 1986).”
BackgroundInfluentialCytokines regulate cysteine cathepsins during TLR responses
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Targeting of Jak/STAT Pathway in Antigen Presenting Cells in Cancer
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Association between serum cathepsin S and mortality in older adults.
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Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice
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Plasma inflammatory cytokines and survival of pancreatic cancer patients
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Molecules Involved in the Crosstalk Between Immune- and Peripheral Nerve Schwann Cells
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“Since apoE deficient Schwann cells exerted an enhanced ability to stimulate proliferation of anti-MPZ T cells, it was suggested that IL-6 diminishes the antigen presenting properties of Schwann cells [126].”
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Effects of immunotherapy of IL-6 and IL-15 plasmids on transmissible venereal tumor in beagles
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Expression and function of ILTs on tolerogenic dendritic cells
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“Recently, it was discovered that the IL-6STAT3 pathway controls the intracellular MHC class II αβ dimer level through cathepsin S activity in DC [39].”
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STAT3: a potential therapeutic target in dendritic cells for the induction of transplant tolerance
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STAT3beta, a distinct isoform from STAT3
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Fms-like tyrosine kinase 3 ligand-dependent dendritic cells in autoimmune inflammation
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Immunotherapy Using Dendritic Cells against Multiple Myeloma: How to Improve?
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“These factors can influence the activation of STAT3 and extracellular signal-regulated kinase (ERK) phosphorylation, resulting in hyperactivation of STAT3 and ERK, which may be responsible for defective DC differentiation [60, 79].”
BackgroundCathepsin S regulates class II MHC processing in human CD4+ HLA-DR+ T cells
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“The enzyme activity of cathepsin B, cathepsin B plus L, cathepsin S, and asparagine endopeptidase (AEP) was measured in vitro as described (21, 22).”
MethodCysteinyl cathepsins in cardiovascular diseases
Zhang, X., Luo, S., Wang, M., & Shi, G. (2020) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2020.140360 · Cited by 36
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Endothelial cells and cathepsins: biochemical and biomechanical regulation
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Regulation of CD4 T‐cell receptor diversity by vaccine adjuvants
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In vivo induction of regulatory T cells for immune tolerance in hemophilia
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“Bone-marrow-derived DCs. Bone-marrow-derived DCs (BMDCs) were generated as previously described (Kitamura et al., 2005).”
MethodSelf-citationOncostatin M Receptor-β Signaling Limits Monocytic Cell Recruitment in Acute Inflammation1
Hams, E., Colmont, C. S., Dioszeghy, V., Hammond, V., Fielding, C., Williams, A., Tanaka, M., Miyajima, A., Taylor, P., Topley, N., et al. (2008) · Journal of Immunology · doi:10.4049/jimmunol.181.3.2174 · Cited by 32
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PMMA particle-mediated DNA vaccine for cervical cancer.
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Tumor secretome shapes the immune landscape during cancer progression
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“31,32 Hyperactivation of STAT3 in MDSCs, M2 macrophages, and Tregs impairs the production of pro-in fl ammatory mediators such as interferon-g , augments the release of tolerogenic mediators, and drives increased expression of immune checkpoint molecules to inhibit effector cell responses.”
Cheng, X. W., Narisawa, M., Wang, H., & Piao, L. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01040-4 · Cited by 35
Metadata
- Authors
- Kitamura, H., Kamon, H., Sawa, S.-I., Park, S.-J., Katunuma, N., Ishihara, K., Murakami, M., & Hirano, T.
- Affiliations
- RIKEN (JP)
- The University of Osaka (JP)
- Tokushima Bunri University (JP)
- Corresponding author
- Hirano, Toshio
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2005-11
- Volume
- 23
- Issue
- 5
- Pages
- 491-502
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2074991167
- Cited by
- 223
- References
- 0
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 9 · 2023: 10 · 2022: 11 · 2021: 18 · 2020: 13 · 2019: 13 · 2018: 14 · 2017: 11 · 2016: 6 · 2015: 6 · 2014: 8 · 2013: 13 · 2012: 10
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- IL-6/STAT3 signaling, cathepsin S, dendritic cells, cystatin C, Ii, T cell activation, gp130, LPS, antigen presentation, CD4+ T cells, immunosuppression
- MeSH terms
- Animals, Histocompatibility Antigens Class II, Cathepsins, Cells, Cultured, Dendritic Cells, Lymphocyte Activation, Mice, Transgenic, RNA, Messenger, Signal Transduction, CD4-Positive T-Lymphocytes, Interleukin-6, Up-Regulation, Cystatins, Dimerization, STAT3 Transcription Factor, Mice
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