Download PDF
Thromb Haemost 2016; 116(02): 317-327
DOI: 10.1160/TH15-12-0917
Endothelium and Angiogenesis
Schattauer GmbH

Interleukin-33 stimulates GM-CSF and M-CSF production by human endothelial cells

Eliana Montanari
1   Department of Internal Medicine II, Medical University of Vienna, Austria
,
Stefan Stojkovic
1   Department of Internal Medicine II, Medical University of Vienna, Austria
2   Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria
,
Christoph Kaun
1   Department of Internal Medicine II, Medical University of Vienna, Austria
,
Christof E. Lemberger
3   Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria
,
Rainer de Martin
3   Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria
,
Sabine Rauscher
4   Core Facilities, Medical University of Vienna, Austria
5   Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Austria
,
Marion Gröger
4   Core Facilities, Medical University of Vienna, Austria
5   Department of Dermatology, Skin and Endothelium Research Division (SERD), Medical University of Vienna, Austria
,
Gerald Maurer
1   Department of Internal Medicine II, Medical University of Vienna, Austria
,
Christoph Neumayer
6   Department of Surgery, Division of Vascular Surgery, Medical University of Vienna, Austria
,
Ihor Huk
6   Department of Surgery, Division of Vascular Surgery, Medical University of Vienna, Austria
,
Kurt Huber
7   3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Vienna, Austria
,
Svitlana Demyanets
1   Department of Internal Medicine II, Medical University of Vienna, Austria
8   Department of Laboratory Medicine, Medical University of Vienna, Austria
,
Johann Wojta
1   Department of Internal Medicine II, Medical University of Vienna, Austria
2   Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria
4   Core Facilities, Medical University of Vienna, Austria
› Author Affiliations Financial support: The research was funded by a grant of the Austrian Science Fund (FWF) to Svitlana Demyanets: FWF-Project number T445-B11. Furthermore, the work was supported by the Association for the Promotion of Research in Arteriosclerosis, Thrombosis and Vascular Biology and by the Ludwig Boltzmann Society.
Further Information

Publication History

Received: 02 December 2015

Accepted after major revision: 24 April 2016

Publication Date:
09 March 2018 (online)

    Permissions and Reprints

Summary

Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in various inflammatory conditions targeting amongst other cells the endothelium. Besides regulating the maturation and functions of myeloid cells, granulocyte macrophage-colony stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) have been shown to play a role in such pathologies too. It was the aim of our study to investigate a possible influence of IL-33 on GM-CSF and M–CSF production by human endothelial cells. IL-33, but not IL-18 or IL-37, stimulated GM-CSF and M-CSF mRNA expression and protein production by human umbilical vein endothelial cells (HUVECs) and human coronary artery ECs (HCAECs) through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in an IL–1-independent way. This effect was inhibited by the soluble form of ST2 (sST2), which is known to act as a decoy receptor for IL-33. The 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor fluvastatin could also be shown to moderately reduce the IL-33-mediated effect on M-CSF, but not on GM-CSF expression. In addition, IL–33, IL-1β, GM-CSF and M-CSF were detected in endothelial cells of human carotid atherosclerotic plaques using immunofluorescence. Upregulation of GM-CSF and M–CSF production by human endothelial cells, an effect that appears to be mediated by NF–κB and to be independent of IL-1, may be an additional mechanism through which IL-33 contributes to inflammatory activation of the vessel wall.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Interleukin-33 - ST2 - endothelial cells - M-CSF - GM-CSF

 

  • References

  • 1 Löhning M, Stroehmann A, Coyle AJ. et al. T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function. Proc Natl Acad Sci U S A 1998; 95: 6930-6935.
    CrossrefPubMedGoogle Scholar
  • 2 Schmitz J, Owyang A, Oldham E. 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.
    CrossrefPubMedGoogle Scholar
  • 3 Allakhverdi Z, Smith DE, Comeau MR. et al. Cutting edge: The ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J Immunol 2007; 179: 2051-2054.
    CrossrefPubMedGoogle Scholar
  • 4 Iikura M, Suto H, Kajiwara N. et al. IL-33 can promote survival, adhesion and cytokine production in human mast cells. Lab Invest 2007; 87: 971-978.
    CrossrefPubMedGoogle Scholar
  • 5 Cherry WB, Yoon J, Bartemes KR. et al. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol 2008; 121: 1484-1490.
    CrossrefPubMedGoogle Scholar
  • 6 Suzukawa M, Koketsu R, Iikura M. et al. Interleukin-33 enhances adhesion, CD11b expression and survival in human eosinophils. Lab Invest 2008; 88: 1245-1253.
    CrossrefPubMedGoogle Scholar
  • 7 Suzukawa M, Iikura M, Koketsu R. et al. An IL-1 cytokine member, IL-33, induces human basophil activation via its ST2 receptor. J Immunol 2008; 181: 5981-5989.
    CrossrefPubMedGoogle Scholar
  • 8 Schneider E, Petit-Bertron AF, Bricard R. et al. IL-33 activates unprimed murine basophils directly in vitro and induces their in vivo expansion indirectly by promoting hematopoietic growth factor production. J Immunol 2009; 183: 3591-3597.
    CrossrefPubMedGoogle Scholar
  • 9 Kurowska-Stolarska M, Stolarski B, Kewin P. et al. IL-33 amplifies the polarisation of alternatively activated macrophages that contribute to airway inflammation. J Immunol 2009; 183: 6469-6477.
    CrossrefPubMedGoogle Scholar
  • 10 Espinassous Q, Garcia-de-Paco E, Garcia-Verdugo I. et al. IL-33 enhances lipopolysaccharide-induced inflammatory cytokine production from mouse macrophages by regulating lipopolysaccharide receptor complex. J Immunol 2009; 183: 1446-1455.
    CrossrefPubMedGoogle Scholar
  • 11 Rank MA, Kobayashi T, Kozaki H. et al. IL-33-activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol 2009; 123: 1047-1054.
    CrossrefPubMedGoogle Scholar
  • 12 Mayuzumi N, Matsushima H, Takashima A.. IL-33 promotes DC development in BM culture by triggering GM-CSF production. Eur J Immunol 2009; 39: 3331-3342.
    CrossrefPubMedGoogle Scholar
  • 13 Choi YS, Choi HJ, Min JK. et al. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood 2009; 114: 3117-3126.
    CrossrefPubMedGoogle Scholar
  • 14 Demyanets S, Konya V, Kastl SP. et al. Interleukin-33 Induces Expression of Adhesion Molecules and Inflammatory Activation in Human Endothelial Cells and in Human Atherosclerotic Plaques. Arterioscler Thromb Vasc Biol 2011; 31: 2080-2089.
    CrossrefPubMedGoogle Scholar
  • 15 Stojkovic S, Kaun C, Heinz M. et al. Interleukin-33 induces urokinase in human endothelial cells: possible impact on angiogenesis. J Thromb Haemost 2014; 12: 948-957.
    CrossrefPubMedGoogle Scholar
  • 16 Hamilton JA.. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 2008; 8: 533-544.
    CrossrefPubMedGoogle Scholar
  • 17 Fixe P, Praloran V.. M-CSF: haematopoietic growth factor or inflammatory cytokine?. Cytokine 1998; 10: 32-37.
    CrossrefPubMedGoogle Scholar
  • 18 Hamilton JA, Achuthan A.. Colony stimulating factors and myeloid cell biology in health and disease. Trends Immunol 2013; 34: 81-89.
    CrossrefPubMedGoogle Scholar
  • 19 Rajavashisth TB, Andalibi A, Territo MC. et al. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature 1990; 344: 254-257.
    CrossrefPubMedGoogle Scholar
  • 20 Fibbe WE, Daha MR, Hiemstra PS. et al. Interleukin 1 and poly(rI).poly(rC) induce production of granulocyte CSF, macrophage CSF, and granulocyte-macrophage CSF by human endothelial cells. Exp Hematol 1989; 17: 229-234.
    PubMedGoogle Scholar
  • 21 Seelentag WK, Mermod JJ, Montesano R. et al. Additive effects of interleukin 1 and tumour necrosis factor-alpha on the accumulation of the three granulocyte and macrophage colony-stimulating factor mRNAs in human endothelial cells. EMBO J 1987; 6: 2261-2265.
    PubMedGoogle Scholar
  • 22 Brown TJ, Liu J, Brashem-Stein C. et al. Regulation of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor expression by oncostatin M. Blood 1993; 82: 33-37.
    PubMedGoogle Scholar
  • 23 Devaraj S, Yun JM, Duncan-Staley C. et al. C-reactive protein induces M-CSF release and macrophage proliferation. J Leukoc Biol 2009; 85: 262-267.
    CrossrefPubMedGoogle Scholar
  • 24 Kosaki K, Ando J, Korenaga R. et al. Fluid shear stress increases the production of granulocyte-macrophage colony-stimulating factor by endothelial cells via mRNA stabilisation. Circ Res 1998; 82: 794-802.
    CrossrefPubMedGoogle Scholar
  • 25 Wojta J, Zoellner H, Gallicchio M. et al. Gamma interferon counteracts interleukin-1 alpha stimulated expression of urokinase-type plasminogen activator in human endothelial cells in vitro. Biochem Biophys Res Commun 1992; 188: 463-469.
    CrossrefPubMedGoogle Scholar
  • 26 Hohensinner PJ, Kaun C, Rychli K. et al. Macrophage colony stimulating factor expression in human cardiac cells is upregulated by tumor necrosis factor-alpha via an NF-kappaB dependent mechanism. J Thromb Haemost 2007; 5: 2520-2528.
    CrossrefPubMedGoogle Scholar
  • 27 Demyanets S, Kaun C, Pentz R. et al. Components of the interleukin-33/ST2 system are differentially expressed and regulated in human cardiac cells and in cells of the cardiac vasculature. J Mol Cell Cardiol 2013; 60: 16-26.
    CrossrefPubMedGoogle Scholar
  • 28 Oitzinger W, Hofer-Warbinek R, Schmid JA. et al. Adenovirus-mediated expression of a mutant IκB kinase 2 inhibits the response of endothelial cells to inflammatory stimuli. Blood 2001; 97: 1611-1617.
    CrossrefPubMedGoogle Scholar
  • 29 Wrighton CJ, Hofer-Warbinek R, Moll T. et al. Inhibition of Endothelial Cell Activation by Adenovirus-mediated Expression of IκBα, an Inhibitor of the Transcription Factor NF-κB. J Exp Med 1996; 183: 1013-1022.
    CrossrefPubMedGoogle Scholar
  • 30 de Martin R, Raidl M, Hofer E. et al. Adenovirus-mediated expression of green fluorescent protein. Gene Ther 1997; 4: 493-495.
    CrossrefPubMedGoogle Scholar
  • 31 Sanada S, Hakuno D, Higgins LJ. et al. IL-33 and ST2 comprise a critical bio-mechanically induced and cardioprotective signaling system. J Clin Invest 2007; 117: 1538-1549.
    CrossrefPubMedGoogle Scholar
  • 32 Miller AM.. Role of IL-33 in inflammation and disease. J Inflamm 2011; 8: 22.
    CrossrefPubMedGoogle Scholar
  • 33 Kondo Y, Yoshimoto T, Yasuda K. et al. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int Immunol 2008; 20: 791-800.
    CrossrefPubMedGoogle Scholar
  • 34 Smithgall MD, Comeau MR, Yoon BR. et al. IL-33 amplifies both Th1– and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells. Int Immunol 2008; 20: 1019-1030.
    CrossrefPubMedGoogle Scholar
  • 35 Zaiss MM, Kurowska-Stolarska M, Böhm C. et al. IL-33 shifts the balance from osteoclast to alternatively activated macrophage differentiation and protects from TNF-alpha-mediated bone loss. J Immunol 2011; 186: 6097-6105.
    CrossrefPubMedGoogle Scholar
  • 36 Boraschi D, Lucchesi D, Hainzl S. et al. IL-37: a new anti-inflammatory cytokine of the IL-1 family. Eur Cytokine Netw 2011; 22: 127-147.
    CrossrefPubMedGoogle Scholar
  • 37 Banchereau J, Pascual V, O’Garra A.. From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines. Nat Immunol 2012; 13: 925-931.
    CrossrefPubMedGoogle Scholar
  • 38 Teng X, Hu Z, Wei X. et al. IL-37 ameliorates the inflammatory process in psoriasis by suppressing proinflammatory cytokine production. J Immunol 2014; 192: 1815-1823.
    CrossrefPubMedGoogle Scholar
  • 39 Chitu V, Stanley ER.. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol 2006; 18: 39-48.
    CrossrefPubMedGoogle Scholar
  • 40 Kleemann R, Zadelaar S, Kooistra T.. Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 2008; 79: 360-376.
    CrossrefPubMedGoogle Scholar
  • 41 Plenz G, Koenig C, Severs NJ. et al. Smooth muscle cells express granulocyte-macrophage colony-stimulating factor in the undiseased and atherosclerotic human coronary artery. Arterioscler Thromb Vasc Biol 1997; 17: 2489-2499.
    CrossrefPubMedGoogle Scholar
  • 42 Ditiatkovski M, Toh BH, Bobik A.. GM-CSF deficiency reduces macrophage PPAR-gamma expression and aggravates atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2006; 26: 2337-2344.
    CrossrefPubMedGoogle Scholar
  • 43 Shaposhnik Z, Wang X, Weinstein M. et al. Granulocyte macrophage colony-stimulating factor regulates dendritic cell content of atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2007; 27: 621-627.
    CrossrefPubMedGoogle Scholar
  • 44 Brochériou I, Maouche S, Durand H. et al. Antagonistic regulation of macrophage phenotype by M-CSF and GM-CSF: implication in atherosclerosis. Atherosclerosis 2011; 214: 316-324.
    CrossrefPubMedGoogle Scholar
  • 45 Zhu SN, Chen M, Jongstra-Bilen J. et al. GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesions. J Exp Med 2009; 206: 2141-2149.
    CrossrefPubMedGoogle Scholar
  • 46 Haghighat A, Weiss D, Whalin MK. et al. Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor exacerbate atherosclerosis in apolipoprotein E-deficient mice. Circulation 2007; 115: 2049-2054.
    CrossrefPubMedGoogle Scholar
  • 47 de Villiers WJ, Smith JD, Miyata M. et al. Macrophage phenotype in mice deficient in both macrophage-colony-stimulating factor (op) and apolipoprotein E. Arterioscler Thromb Vasc Biol 1998; 18: 631-640.
    CrossrefPubMedGoogle Scholar
  • 48 Shindo J, Ishibashi T, Yokoyama K. et al. Granulocyte-macrophage colony-stimulating factor prevents the progression of atherosclerosis via changes in the cellular and extracellular composition of atherosclerotic lesions in watanabe heritable hyperlipidemic rabbits. Circulation 1999; 99: 2150-2156.
    CrossrefPubMedGoogle Scholar
  • 49 Inoue I, Inaba T, Motoyoshi K. et al. Macrophage colony stimulating factor prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbits. Atherosclerosis 1992; 93: 245-254.
    CrossrefPubMedGoogle Scholar
  • 50 Subramanian M, Thorp E, Tabas I.. Identification of a non-growth factor role for GM-CSF in advanced atherosclerosis: promotion of macrophage apoptosis and plaque necrosis through IL-23 signaling. Circ Res 2015; 116: e13-24.
    CrossrefPubMedGoogle Scholar
  • 51 Zbinden S, Zbinden R, Meier P. et al. Safety and efficacy of subcutaneous-only granulocyte-macrophage colony-stimulating factor for collateral growth promotion in patients with coronary artery disease. J Am Coll Cardiol 2005; 46: 1636-1642.
    CrossrefPubMedGoogle Scholar
  • 52 Saitoh T, Kishida H, Tsukada Y. et al. Clinical significance of increased plasma concentration of macrophage colony-stimulating factor in patients with angina pectoris. J Am Coll Cardiol 2000; 35: 655-665.
    CrossrefPubMedGoogle Scholar
  • 53 Hohensinner PJ, Rychli K, Zorn G. et al. Macrophage-modulating cytokines predict adverse outcome in heart failure. Thromb Haemost 2010; 103: 435-441.
    Article in Thieme ConnectPubMedGoogle Scholar