Abstract
ST2 protein is a soluble splicing variant of ST2L protein, which is the receptor for interleukin-33 (IL-33). Previously, we reported that soluble ST2 suppressed the signal transduction of lipopolysaccharide (LPS) and cytokine production in monocytic cells. To investigate whether or not this inhibitory effect occurs in dendritic cells, which are the key players in innate and adaptive immunity, human monocyte-derived dendritic cells were pre-treated with soluble ST2 protein before LPS stimulation. Although soluble ST2 did not attenuate the LPS-induced maturation of dendritic cells, pre-treatment with soluble ST2 suppressed cytokine production and inhibited LPS signaling. Moreover, the proliferation of naive T cells was inhibited significantly by soluble ST2 pre-treatment. IL-33 had little effect on the cytokine production of immature monocyte-derived dendritic cells. Furthermore, soluble ST2 protein was internalized into dendritic cells, suggesting that soluble ST2 protein acts by a noncanonical mechanism other than the sequestration of IL-33.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005; 23: 479–490.
Hayakawa H, Hayakawa M, Kume A, Tominaga S . Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem 2007; 282: 26369–26380.
Oshikawa K, Kuroiwa K, Tago K, Iwahana H, Yanagisawa K, Ohno S et al. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am J Respir Crit Care Med 2001; 164: 277–281.
Lloyd CM . IL-33 family members and asthma - bridging innate and adaptive immune responses. Curr Opin Immunol 2010; 22: 800–806.
Kuroiwa K, Arai T, Okazaki H, Minota S, Tominaga S . Identification of human ST2 protein in the sera of patients with autoimmune diseases. Biochem Biophys Res Commu 2001; 284: 1104–1108.
Talabot-Ayer D, McKee T, Gindre P, Bas S, Baeten DL, Gabay C et al. Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Joint Bone Spine 2012; 79: 32–37.
Weinberg EO, Shimpo M, Hurwitz S, Tominaga S, Rouleau JL, Lee RT . Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation 2003; 107: 721–726.
Daniels LB, Clopton P, Iqbal N, Tran K, Maisel AS . Association of ST2 levels with cardiac structure and function and mortality in outpatients. Am Heart J 2010; 160: 721–728.
Tajima S, Oshikawa K, Tominaga S, Sugiyama Y . The increase in serum soluble ST2 protein upon acute exacerbation of idiopathic pulmonary fibrosis. Chest 2003; 124: 1206–1214.
Sweet MJ, Leung BP, Kang D, Sogaard M, Schulz K, Trajkovic V et al. A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression. J Immunol 2001; 166: 6633–6639.
Yin H, Li XY, Yuan BH, Zhang BB, Hu SL, Gu HB et al. Adenovirus-mediated overexpression of soluble ST2 provides a protective effect on lipopolysaccharide-induced acute lung injury in mice. Clin Exp Immunol 2011; 164: 248–255.
Takezako N, Hayakawa M, Hayakawa H, Aoki S, Yanagisawa K, Endo H et al. ST2 suppresses IL-6 production via the inhibition of IkB degradation induced by the LPS signal in THP-1 cells. Biochem Biophys Res Commun 2006; 341: 425–432.
Verhasselt V, Buelens C, Willems F, de Groote D, Haeffner-Cavaillon N, Goldman M . Bacterial lipopolysaccharide stimulates the production of cytokines and the expression of costimulatory molecules by human peripheral blood dendritic cells: evidence for a soluble CD14-dependent pathway. J Immunol 1997; 158: 2919–2925.
Banchereau J, Steinman RM . Dendritic cells and the control of immunity. Nature 1998; 392: 245–252.
Rank MA, Kobayashi T, Kozaki H, Bartemes KR, Squillace DL, Kita H . IL-33-activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol 2009; 123: 1047–1054.
Besnard AG, Togbe D, Guillou N, Erard F, Quesniaux V, Ryffel B . IL-33-activated dendritic cells are critical for allergic airway inflammation. Eur J Immunol 2011; 41: 1675–1686.
Nguyen XD, Eichler H, Dugrillon A, Piechaczek C, Braun M, Klüter H . Flow cytometric analysis of T cell proliferation in a mixed lymphocyte reaction with dendritic cells. J Immunol Methods 2003; 275: 57–68.
Yamasaki M, Hashiguchi N, Tsukamoto T, Osumi T . Variant forms of green and blue fluorescent proteins adapted for the use in mammalian cells. Bioimages 1998; 6: 1–7.
Swanson JA, Watts C . Macropinocytosis. Trends Cell Biol 1995; 5: 424–428.
Meier O, Boucke K, Hammer SV, Keller S, Stidwill RP, Hemmi S et al. Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake. J Cell Biol 2002; 158: 1119–1131.
Sutherland MD, Kozel TR . Macrophage uptake, intracellular localization, and degradation of poly-g-D-glutamic acid, the capsular antigen of Bacillus anthracis. Infect Immun 2009; 77: 532–538.
Means TK, Hayashi F, Smith KD, Aderem A, Luster AD . The toll-like receptor 5 stimulus bacterial fragellin induces maturation and chemokine production in human dendritic cells. J Immunol 2003; 170: 5165–5175.
Sanada S, Hakuno D, Higgins LJ, Schreiter ER, Andrew N . J. McKenzie ANJ et al. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J Clin Invest 2007; 117: 1538–1549.
Hoogerwerf JJ, Tanck MW, van Zoelen MA, Wittebole X, Laterre PF, van der Poll T . Soluble ST2 plasma concentrations predict mortality in severe sepsis. Intensive Care Med 2010; 36: 630–637.
Schreibelt G, Tel J, Sliepen KH, Benitez-Ribas D, Figdor CG, Adema GJ et al. Toll-like receptor expression and function in human dendritic cell subsets: implications for dendritic cell-based anti-cancer immunotherapy. Cancer Immunol Immunother 2010; 10: 1573–1582.
Zanoni I, Granucci F . Regulation of antigen uptake, migration, and lifespan of dendritic cell by Toll-like receptors. J Mol Med 2010; 9: 873–880.
Kagan JC, Su T, Horng T, Chow A, Akira S, Medzhitov R . TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat Immunol 2008; 9: 361–368.
Husebye H, Halaas Ø, Stenmark H, Tunheim G, Sandanger Ø, Bogen B et al. Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity. EMBO J 2006; 25: 683–692.
Chiang CY, Veckman V, Limmer K, David M . Phospholipase Cγ-2 and intracellular calcium are required for lipopolysaccharide-induced Toll-like receptor 4 (TLR4) endocytosis and interferon regulatory factor 3 (IRF3) Activation. J Biol Chem 2012; 287: 3704–3709.
Miller AM . Role of IL-33 in inflammation and disease. J Inflamm (Lond) 2011; 8: 22.
Martinez-Rumayor A, Camargo CA, Green SM, Baggish AL, O'Donoghue M, Januzzi JL . Soluble ST2 plasma concentrations predict 1-year mortality in acutely dyspneic emergency department patients with pulmonary disease. Am J Clin Pathol 2008; 130: 578–584.
Alves-Filho JC, Sônego F, Souto FO, Freitas A, Verri WA Jr, Auxiliadora-Martins M et al. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat Med 2010; 16: 708–712.
Reddy RC, Chen GH, Tekchandani PK, Standiford TJ . Sepsis-induced immunosuppression: from bad to worse. Immunol Res 2001; 24: 273–287.
Acknowledgements
We thank Dr Morisada Hayakawa, Dr Nobuhiko Kamoshita and Dr Masaki Kashiwada, Jichi Medical University, for the helpful discussions. The authors are grateful to Ms Reiko Izawa and Ms Chihiro Aoki for their excellent technical support and clerical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nagata, A., Takezako, N., Tamemoto, H. et al. Soluble ST2 protein inhibits LPS stimulation on monocyte-derived dendritic cells. Cell Mol Immunol 9, 399–409 (2012). https://doi.org/10.1038/cmi.2012.29
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cmi.2012.29
Keywords
This article is cited by
-
Exogenous interleukin 33 enhances the brain’s lymphatic drainage and toxic protein clearance in acute traumatic brain injury mice
Acta Neuropathologica Communications (2023)
-
Role of the IL-33-ST2 axis in sepsis
Military Medical Research (2017)
-
Relapsing-remitting multiple sclerosis patients display an altered lipoprotein profile with dysfunctional HDL
Scientific Reports (2017)
-
Prothymosin α and a prothymosin α-derived peptide enhance TH1-type immune responses against defined HER-2/neu epitopes
BMC Immunology (2013)
-
The Evolutionary Role of the IL-33/ST2 System in Host Immune Defence
Archivum Immunologiae et Therapiae Experimentalis (2013)