Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Immunology
Published in: BMC Immunology 1/2011

Open Access 01-12-2011 | Research article

Adaptor protein Shc acts as an immune-regulator for the LPS-stimulated maturation of bone marrow-derived dendritic cells

Authors: Kuang-Den Chen, Li-Wen Hsu, Shigeru Goto, Chin-Wei Yeh, Toshiaki Nakano, Chia-Yun Lai, Yen-Chen Chang, Chiung-Hui Hou, Chih-Chi Wang, Yu-Fan Cheng, King-Wah Chiu, Chih-Che Lin, Chao-Long Chen

Published in: BMC Immunology | Issue 1/2011

Login to get access

Abstract

Background

The Shc isoforms is known to mediate immune responses and has been indicated as a negative regulator of autoimmunity and lymphocyte activation. We aimed to evaluate the immune-regulatory role of Shc in rat bone marrow-derived DCs in the maturation process triggered by LPS.

Results

We found that, in response to LPS, expression of Shc proteins was induced and that neutralization of Shc inhibited the LPS-induced transient phosphorylation of p52Shc on pTyr239/240 in DCs of Lewis (LEW; RT1l) rats. Moreover, the significantly enhanced expression of IL-10 and the surface level of costimulatory molecule CD80, as well as suppressed expression of IL-6 and IL-12 in the Shc-silenced DCs were also observed. Similar IκB phosphorylation occurred in Shc-silenced DCs primed by LPS, indicating Shc is not associated with NF-κB pathway. We further demonstrate that Shc blockade on LPS-treated DCs results in significant increase of the overall STAT3 phosphorylation and the relative levels of phospho-STAT3 in the nuclear fraction. STAT3 activation by LPS with or without Shc blockade was totally abolished by SU6656, a selective Src family kinases inhibitor, underscoring the critical role of Src-mediated activation.

Conclusions

We conclude that Shc blockade in LPS-primed DC leads to the development of tolerogenic DC via Src-dependent STAT3 activation and that adaptor protein Shc might play a pivotal role in mediating immunogenic and tolerogenic properties of DCs.
Appendix
Available only for authorised users
Literature
1.
Steinman RM, Kaplan G, Witmer MD, Cohn ZA: Identification of a novel cell type in peripheral lymphoid organs of mice. V. Purification of spleen dendritic cells, new surface markers, and maintenance in vitro. J Exp Med. 1979, 149: 1-16. 10.1084/jem.149.1.1.PubMedCrossRef
2.
Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature. 1998, 392: 245-252. 10.1038/32588.PubMedCrossRef
3.
Lanzavecchia A, Sallusto F: Regulation of T cell immunity by dendritic cells. Cell. 2001, 106: 263-266. 10.1016/S0092-8674(01)00455-X.PubMedCrossRef
4.
Maldonado-Lopez R, Moser M: Dendritic cell subsets and the regulation of Th1/Th2 responses. Semin Immunol. 2001, 13: 275-282. 10.1006/smim.2001.0323.PubMedCrossRef
5.
Moser M, Murphy KM: Dendritic cell regulation of TH1-TH2 development. Nat Immunol. 2000, 1: 199-205.PubMedCrossRef
6.
Chakraborty A, Li L, Chakraborty NG, Mukherji B: Stimulatory and inhibitory maturation of human macrophage-derived dendritic cells. Pathobiol. 1999, 67: 282-286. 10.1159/000028080.CrossRef
7.
Chakraborty A, Li L, Chakraborty NG, Mukherji B: Stimulatory and inhibitory maturation of human myeloid dendritic cells. Clin Immunol. 2000, 94: 88-98. 10.1006/clim.1999.4826.PubMedCrossRef
8.
Corinti S, Albanesi C, la Sala A, Pastore S, Girolomoni G: Regulatory activity of autocrine IL-10 on dendritic cell functions. J Immunol. 2001, 166: 4312-4318.PubMedCrossRef
9.
Willems F, Marchant A, Delville JP, Gérard C, Delvaux A, Velu T, de Boer M, Goldman M: Interleukin-10 inhibits B7 and intercellular adhesion molecule-1 expression on human monocytes. Eur J Immunol. 1994, 24: 1007-1009. 10.1002/eji.1830240435.PubMedCrossRef
10.
Allavena P, Piemonti L, Longoni D, Bernasconi S, Stoppacciaro A, Ruco L, Mantovani A: IL-10 prevents the generation of dendritic cells from CD14+ blood monocytes, promotes the differentiation to mature macrophages and stimulates endocytosis of FITC-dextran. Adv Exp Med Biol. 1997, 417: 323-327.PubMedCrossRef
11.
De Smedt T, Van Mechelen M, De Becker G, Urbain J, Leo O, Moser M: Effect of interleukin-10 on dendritic cell maturation and function. Eur J Immunol. 1997, 27: 1229-1235. 10.1002/eji.1830270526.PubMedCrossRef
12.
Battaglia M, Gregori S, Bacchetta R, Roncarolo MG: Tr1 cells: from discovery to their clinical application. Semin Immunol. 2006, 18: 120-127. 10.1016/j.smim.2006.01.007.PubMedCrossRef
13.
Zhou X, Schmidtke P, Zepp F, Meyer CU: Boosting interleukin-10 production: therapeutic effects and mechanisms. Curr Drug Targets Immune Endocr Metabol Disord. 2005, 5: 465-575. 10.2174/156800805774912926.PubMedCrossRef
14.
Sallusto F, Lanzavecchia A: Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994, 179: 1109-1118. 10.1084/jem.179.4.1109.PubMedCrossRef
15.
Stefanova I, Corcoran ML, Horak EM, Wahl LM, Bolen JB, Horak ID: Lipopolysaccharide induces activation of CD14-associated protein tyrosine kinase p53/56lyn. J Biol Chem. 1993, 268: 20725-20728.PubMed
16.
Ravichandran KS: Signaling via Shc family adapter proteins. Oncogene. 2001, 20: 6322-6330. 10.1038/sj.onc.1204776.PubMedCrossRef
17.
Chen KD, Li YS, Kim M, Li S, Yuan S, Chien S, Shyy JY: Mechanotransduction in response to shear stress. Roles of receptor tyrosine kinases, integrins, and Shc. J Biol Chem. 1999, 274: 18393-18400. 10.1074/jbc.274.26.18393.PubMedCrossRef
18.
Kavanaugh WM, Williams LT: An alternative to SH2 domains for binding tyrosine-phosphorylated proteins. Science. 1994, 266: 1862-1865. 10.1126/science.7527937.PubMedCrossRef
19.
Finetti F, Pellegrini M, Ulivieri C, Savino MT, Paccagnini E, Ginanneschi C, Lanfrancone L, Pelicci PG, Baldari CT: The proapoptotic and antimitogenic protein p66SHC acts as a negative regulator of lymphocyte activation and autoimmunity. Blood. 2008, 111: 5017-5027. 10.1182/blood-2007-12-130856.PubMedCrossRef
20.
Pulendran B, Kumar P, Cutler CW, Mohamadzadeh M, Van Dyke T, Banchereau J: Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo. J Immunol. 2001, 167: 5067-5076.PubMedPubMedCentralCrossRef
21.
Pulendran B: Variegation of the immune response with dendritic cells and pathogen recognition receptors. J Immunol. 2005, 174: 2457-2465.PubMedCrossRef
22.
Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998, 282: 2085-2088.PubMedCrossRef
23.
Means TK, Golenbock DT, Fenton MJ: The biology of Toll-like receptors. Cytokine Growth Factor Rev. 2000, 11: 219-232. 10.1016/S1359-6101(00)00006-X.PubMedCrossRef
24.
Underhill DM, Ozinsky A, Hajjar AM, Stevens A, Wilson CB, Bassetti M, Aderem A: The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature. 1999, 401: 811-815. 10.1038/44605.PubMedCrossRef
25.
Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, Bleharski JR, Maitland M, Norgard MV, Plevy SE, Smale ST, Brennan PJ, Bloom BR, Godowski PJ, Modlin RL: Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science. 1999, 285: 732-736. 10.1126/science.285.5428.732.PubMedCrossRef
26.
Means TK, Wang S, Lien E, Yoshimura A, Golenbock DT, Fenton MJ: Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J Immunol. 1999, 163: 3920-3927.PubMed
27.
Kapsenberg ML: Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol. 2003, 3: 984-993. 10.1038/nri1246.PubMedCrossRef
28.
Janssen E, Zhang W: Adaptor proteins in lymphocyte activation. Curr Opin Immunol. 2003, 15: 269-276. 10.1016/S0952-7915(03)00044-X.PubMedCrossRef
29.
Lee MS, Kim YJ: Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu Rev Biochem. 2007, 76: 447-480. 10.1146/annurev.biochem.76.060605.122847.PubMedCrossRef
30.
Li X, Qin J: Modulation of Toll-interleukin-1 receptor mediated signaling. J Mol Med. 2005, 83: 258-266. 10.1007/s00109-004-0622-4.PubMedCrossRef
31.
Pacini S, Pellegrini M, Migliaccio E, Patrussi L, Ulivieri C, Ventura A, Carraro F, Naldini A, Lanfrancone L, Pelicci P, Baldari CT: p66SHC promotes apoptosis and antagonizes mitogenic signaling in T cells. Mol Cell Biol. 2004, 24: 1747-1757. 10.1128/MCB.24.4.1747-1757.2004.PubMedPubMedCentralCrossRef
32.
Salcini AE, McGlade J, Pelicci G, Nicoletti I, Pawson T, Pelicci PG: Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins. Oncogene. 1994, 9: 2827-2836.PubMed
33.
Gotoh N, Tojo A, Shibuya M: A novel pathway from phosphorylation of tyrosine residues 239/240 of Shc, contributing to suppress apoptosis by IL-3. EMBO J. 1996, 15: 6197-6204.PubMedPubMedCentral
34.
Patrussi L, Savino MT, Pellegrini M, Paccani SR, Migliaccio E, Plyte S, Lanfrancone L, Pelicci PG, Baldari CT: Cooreration and selectivity of the two Grb2 binding sites of p52Shc in T-cell antigen receptor signaling to ras family GTPases and Myc-dependent survival. Oncogene. 2005, 24: 2218-2228. 10.1038/sj.onc.1208384.PubMedCrossRef
35.
Wan H, Versnel MA, Leijten LM, van Helden-Meeuwsen CG, Fekkes D, Leenen PJ, Khan NA, Benner R, Kiekens RC: Chorionic gonadotropin induces dendritic cells to express a tolerogenic phenotype. J Leukoc Biol. 2008, 83: 894-901. 10.1189/jlb.0407258.PubMedCrossRef
36.
Murray P: The primary mechanism of the IL-10-regulated anti-inflammatory response is to selectively inhibit transcription. Proc Natl Acad Sci USA. 2005, 102: 8686-8691. 10.1073/pnas.0500419102.PubMedPubMedCentralCrossRef
37.
Murray P: Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Curr Opin Pharmacol. 2006, 6: 379-386. 10.1016/j.coph.2006.01.010.PubMedCrossRef
38.
Hoentjen F, Sartor RB, Ozaki M, Jobin C: STAT3 regulates NF-kappaB recruitment to the IL-12p40 promoter in dendritic cells. Blood. 2005, 105: 689-696. 10.1182/blood-2004-04-1309.PubMedCrossRef
39.
40.
Riley JK, Takeda K, Akira S, Schreiber RD: Interleukin-10 receptor signaling through the JAK-STAT pathway. Requirement for two distinct receptor-derived signals for anti-inflammatory action. J Biol Chem. 1999, 274: 16513-16521. 10.1074/jbc.274.23.16513.PubMedCrossRef
41.
Land WG: Innate immunity-mediated allograft rejection and strategies to prevent it. Transplant Proc. 2007, 39: 667-672. 10.1016/j.transproceed.2007.01.052.PubMedCrossRef
42.
Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci PG: A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell. 1992, 70: 1165-1174.CrossRef
43.
Liu Y, Sweet DT, Irani-Tehrani M, Maeda N, Tzima E: Shc coordinates signals from intercellular junctions and integrins to regulate flow-induced inflammation. J Cell Biol. 2008, 182: 185-196. 10.1083/jcb.200709176.PubMedPubMedCentralCrossRef
44.
Segura E, Nicco C, Lombard B, Veron P, Raposo G, Batteux F, Amigorena S, Thery C: ICAM-1 on exosomes from mature dendritic cells is critical for efficient naïve T-cell priming. Blood. 2005, 106: 216-223. 10.1182/blood-2005-01-0220.PubMedCrossRef
45.
Hsu LW, Goto S, Nakano T, Lai CY, Kao YH, Lin YC, Kawamoto S, Ono K, Lord R, Goto T, Omori N, Sato S, Chiang KC, Chen SH, Jawan B, Cheng YF, Chiu KW, Chen CL: The effects of anti-histone H1 antibody on immune cells responsible for rejection reaction. Mol Immunol. 2005, 42: 1155-1164. 10.1016/j.molimm.2004.11.010.PubMedCrossRef
46.
Hsu LW, Chen CL, Nakano T, Lai CY, Chiang KC, Lin YC, Kao YH, Chen SH, Goto T, Sung WC, Yang CH, Cheng YF, Jawan B, Chiu KW, Goto S: The role of a nuclear protein, histone H1, on signaling pathways for the maturation of dendritic cells. Clin Exp Immunol. 2008, 152: 576-584. 10.1111/j.1365-2249.2008.03652.x.PubMedPubMedCentralCrossRef
Metadata
Title
Adaptor protein Shc acts as an immune-regulator for the LPS-stimulated maturation of bone marrow-derived dendritic cells
Authors
Kuang-Den Chen
Li-Wen Hsu
Shigeru Goto
Chin-Wei Yeh
Toshiaki Nakano
Chia-Yun Lai
Yen-Chen Chang
Chiung-Hui Hou
Chih-Chi Wang
Yu-Fan Cheng
King-Wah Chiu
Chih-Che Lin
Chao-Long Chen
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2011
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/1471-2172-12-32

Other articles of this Issue 1/2011

BMC Immunology 1/2011 Go to the issue

Research article

Shb deficient mice display an augmented TH2 response in peripheral CD4+ T cells

Research article

Goishi tea consumption inhibits airway hyperresponsiveness in BALB/c mice

Research article

Blockade of leukocyte haptokinesis and haptotaxis by ketoprofen, diclofenac and SC-560

Research article

Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension

Research article

CTLA4 is expressed on mature dendritic cells derived from human monocytes and influences their maturation and antigen presentation

Research article

Autoreactive marginal zone B cells enter the follicles and interact with CD4+ T cells in lupus-prone mice
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits