Interleukin-6: From basic biology to selective blockade of pro-inflammatory activities

Seminars in Immunology

Volumn 26, Issue 1, 2014, Pages 2-12

  Scheller, Jürgen ^a   Garbers, Christoph ^b   Rose John, Stefan ^b  

^a Department of Orthopedic Surgery   (Germany)

^b UNIVERSITY OF KIEL   (Germany)

Author keywords

ADAM17; Inflammation; Interleukin 6; Sgp130Fc; Soluble receptor; Trans signaling

Indexed keywords

GLYCOPROTEIN GP 130; INTERLEUKIN 6; INTERLEUKIN 6 RECEPTOR;

ATHEROSCLEROSIS; COLON CANCER; HUMAN; INFLAMMATION; INFLAMMATORY BOWEL DISEASE; OVARY CANCER; PANCREAS CANCER; PANCREATITIS; PERITONITIS; REVIEW; RHEUMATOID ARTHRITIS;

ADAM17; INFLAMMATION; INTERLEUKIN-6; SGP130FC; SOLUBLE RECEPTOR; TRANS-SIGNALING;

ANIMALS; HUMANS; INFLAMMATION; INFLAMMATION MEDIATORS; INTERLEUKIN-6; NEOPLASMS; RECEPTORS, INTERLEUKIN-6; RECOMBINANT FUSION PROTEINS; SIGNAL TRANSDUCTION;

EID: 84896488117     PISSN: 10445323     EISSN: 10963618     Source Type: Journal    
DOI: 10.1016/j.smim.2013.11.002     Document Type: Review

References (126)

1. Alonzi T., Fattori E., Lazzaro D., Costa P., Probert L., Kollias G., et al. Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 1998, 187:461-468.
2. Ohshima S., Saeki Y., Mima T., Sasai M., Nishioka K., Nomura S., et al. Interleukin-6 plays a key role in the development of antigen-induced arthritis. Proc Natl Acad Sci U S A 1998, 95:8222-8226.
3. Robak T., Gladalska A., Stepien H., Robak E. Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis. Mediators Inflamm 1998, 7:347-353.
4. Tanaka T., Narazaki M., Kishimoto T. Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 2012, 52:199-219.
5. Melton L., Coombs A. Actemra poised to launch IL-6 inhibitors. Nat Biotechnol 2008, 26:957-959.
6. Yao X., Huang J., Zhong H., Shen N., Faggioni R., Fung M., et al. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmocol Ther 2013, 10.1016/j.pharmthera.2013.09.004.
7. Garbers C., Hermanns H.M., Schaper F., Müller-Newen G., Grötzinger J., Rose-John S., et al. Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev 2012, 23:85-97.
8. Garbers C., Scheller J. Interleukin-6 and interleukin-11: same but different. Biol Chem 2013, 394:1145-1161.
9. Lust J., Donovan K., Kline M., Greipp P., Kyle R., Maihle N. Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine 1992, 4:96-100.
10. Müllberg J., Schooltink H., Stoyan T., Heinrich P., Rose-John S. Protein kinase C activity is rate limiting for shedding of the interleukin-6 receptor. Biochem Biophys Res Commun 1992, 189:794-800.
11. Müllberg J., Schooltink H., Stoyan T., Günther M., Graeve L., Buse G., et al. The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol 1993, 23:473-553.
12. Müllberg J., Oberthur W., Lottspeich F., Mehl E., Dittrich E., Graeve L., et al. The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site. J Immunol 1994, 152:4958-4968.
13. Rose-John S., Heinrich P.C. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J 1994, 300:281-290.
14. Fischer M., Goldschmitt J., Peschel C., Brakenhoff J.P., Kallen K.J., Wollmer A., et al. A bioactive designer cytokine for human hematopoietic progenitor cell expansion. Nat Biotechnol 1997, 15:142-145.
15. Jostock T., Mullberg J., Ozbek S., Atreya R., Blinn G., Voltz N., et al. Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur J Biochem 2001, 268:160-167.
16. Jones S.A., Scheller J., Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 2011, 121:3375-3383.
17. Khokha R., Murthy A., Weiss A. Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol 2013, 13:649-665.
18. Murphy G., Murthy A., Khokha R. Clipping, shedding and RIPping keep immunity on cue. Trends Immunol 2008, 29:75-82.
19. Murphy G. Regulation of the proteolytic disintegrin metalloproteinases, the 'Sheddases'. Semin Cell Dev Biol 2009, 20:138-145.
20. Gaillard J., Bataille R., Brailly H., Zuber C., Yasukawa K., Attal M., et al. Increased and highly stable levels of functional soluble interleukin-6 receptor in sera of patients with monoclonal gammopathy. Eur J Immunol 1993, 23:820-824.
21. Hartmann D., de Strooper B., Serneels L., Craessaerts K., Herreman A., Annaert W., et al. The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum Mol Genet 2002, 11:2615-2624.
22. Peschon J., Slack J., Reddy P., Stocking K., Sunnarborg S., Lee D., et al. An essential role for ectodomain shedding in mammalian development. Science 1998, 282:1281-1284.
23. Scheller J., Chalaris A., Garbers C., Rose-John S. ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol 2011, 32:380-387.
24. Saftig P., Reiss K., The A Disintegrin And Metalloproteases ADAM10 and ADAM17: novel drug targets with therapeutic potential? Eur J Cell Biol 2011, 90:527-535.
25. Pruessmeyer J., Ludwig A. The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer. Semin Cell Dev Biol 2009, 20:164-174.
26. Ludwig A., Hundhausen C., Lambert M., Broadway N., Andrews R., Bickett D., et al. Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb Chem High Throughput Screen 2005, 8:161-171.
27. Chalaris A., Rabe B., Paliga K., Lange H., Laskay T., Fielding C.A., et al. Apoptosis is a natural stimulus of IL6R shedding and contributes to the pro-inflammatory trans-signaling function of neutrophils. Blood 2007, 110:1748-1755.
28. Garbers C., Jänner N., Chalaris A., Moss M.L., Floss D.M., Meyer D., et al. Species specificity of ADAM10 and ADAM17 proteins in interleukin-6 (IL-6) trans-signaling and novel role of ADAM10 in inducible IL-6 receptor shedding. J Biol Chem 2011, 286:14804-14811.
29. Matthews V., Schuster B., Schutze S., Bussmeyer I., Ludwig A., Hundhausen C., et al. Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE). J Biol Chem 2003, 278:38829-38839.
30. Jones S., Horiuchi S., Novick D., Yamamoto N., Fuller G. Shedding of the soluble IL-6 receptor is triggered by Ca2+ mobilization, while basal release is predominantly the product of differential mRNA splicing in THP-1 cells. Eur J Immunol 1998, 28:3514-3522.
31. Moss M., Bomar M., Liu Q., Sage H., Dempsey P., Lenhart P., et al. The ADAM10 prodomain is a specific inhibitor of ADAM10 proteolytic activity and inhibits cellular shedding events. J Biol Chem 2007, 282:35712-35721.
32. Gonzales P., Solomon A., Miller A., Leesnitzer M., Sagi I., Milla M. Inhibition of the tumor necrosis factor-alpha-converting enzyme by its pro domain. J Biol Chem 2004, 279:31638-31645.
33. Baran P., Nitz R., Grötzinger J., Scheller J., Garbers C. Minimal interleukin (IL-)6 receptor stalk composition for IL-6R shedding and IL-6 classic signaling. J Biol Chem 2013, 288:14756-14768.
34. Lorenzen I., Lokau J., Düsterhoft S., Trad A., Garbers C., Scheller J., et al. The membrane-proximal domain of A Disintegrin And Metalloprotease 17 (ADAM17) is responsible for recognition of the interleukin-6 receptor and interleukin-1 receptor II. FEBS Lett 2012, 586:1093-1100.
35. Willems S., Tape C., Stanley P., Taylor N., Mills I., Neal D., et al. Thiol isomerases negatively regulate the cellular shedding activity of ADAM17. Biochem J 2010, 428:439-450.
36. Düsterhöft S., Jung S., Hung C-W., Tholey A., Sönnichsen F., Grötzinger J., et al. Membrane-proximal domain of a disintegrin and metalloprotease-17 represents the putative molecular switch of its shedding activity operated by protein-disulfide isomerase. J Am Chem Soc 2013, 135:5776-5781.
37. Chalaris A., Gewiese J., Paliga K., Fleig L., Schneede A., Krieger K., et al. ADAM17-mediated shedding of the IL6R induces cleavage of the membrane stub by gamma-secretase. Biochim Biophys Acta 2010, 1803:234-245.
38. Hurst S.M., Wilkinson T.S., McLoughlin R.M., Jones S., Horiuchi S., Yamamoto N., et al. IL-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity 2001, 14:705-714.
39. Briso E., Dienz O., Rincon M. Cutting edge: soluble IL-6R is produced by IL-6R ectodomain shedding in activated CD4 T cells. J Immunol 2008, 180:7102-7106.
40. Bank U., Reinhold D., Schneemilch C., Kunz D., Synowitz H., Ansorge S. Selective proteolytic cleavage of IL-2 receptor and IL-6 receptor ligand binding chains by neutrophil-derived serine proteases at foci of inflammation. J Interferon Cytokine Res 1999, 19:1277-1287.
41. Vollmer P., Walev I., Rose-John S., Bhakdi S. Novel pathogenic mechanism of microbial metalloproteinases: liberation of membrane-anchored molecules in biologically active form exemplified by studies with the human interleukin-6 receptor. Infect Immun 1996, 64:3646-3651.
42. Oleksy A., Banbula A., Bugno M., Travis J., Potempa J. Proteolysis of interleukin-6 receptor (IL-6R) by Porphyromonas gingivalis cysteine proteinases (gingipains) inhibits interleukin-6-mediated cell activation. Microb Pathog 2002, 32:173-181.
43. Walev I., Vollmer P., Palmer M., Bhakdi S., Rose-John S. Pore-forming toxins trigger shedding of receptors for interleukin 6 and lipopolysaccharide. Proc Natl Acad Sci U S A 1996, 93:7882-7887.
44. Moss M., Sklair-Tavron L., Nudelman R. Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheumatol 2008, 4:300-309.
45. Garbers C., Spudy B., Aparicio-Siegmund S., Waetzig G.H., Sommer J., Holscher C., et al. An interleukin-6 receptor-dependent molecular switch mediates signal transduction of the IL-27 cytokine subunit p28 (IL-30) via a gp130 protein receptor homodimer. J Biol Chem 2013, 288:4346-4354.
46. Rose-John S. GP130 stimulation and the maintenance of stem cells. Trends Biotechnol 2002, 20:417-419.
47. Klouche M., Bhakdi S., Hemmes M., Rose-John S. Novel path to activation of vascular smooth muscle cells: up-regulation of gp130 creates an autocrine activation loop by IL-6 and its soluble receptor. J Immunol 1999, 163:4583-4589.
48. Romano M., Sironi M., Toniatti C., Polentarutti N., Fruscella P., Ghezzi P., et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 1997, 6:315-325.
49. Peters M., Jacobs S., Ehlers M., Vollmer P., Mullberg J., Wolf E., et al. The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6. J Exp Med 1996, 183:1399-1406.
50. Peters M., Schirmacher P., Goldschmitt J., Odenthal M., Peschel C., Fattori E., et al. Extramedullary expansion of hematopoietic progenitor cells in interleukin (IL)-6-sIL-6R double transgenic mice. J Exp Med 1997, 185:755-766.
51. Schirmacher P., Peters M., Ciliberto G., Blessing M., Lotz J., Meyer zum Buschenfelde K.H., et al. Hepatocellular hyperplasia, plasmacytoma formation, and extramedullary hematopoiesis in interleukin (IL)-6/soluble IL-6 receptor double-transgenic mice. Am J Pathol 1998, 153:639-648.
52. Brunello A., Weissenberger J., Kappeler A., Vallan C., Peters M., Rose-John S., et al. Astrocytic alterations in interleukin-6/soluble interleukin-6 receptor alpha double-transgenic mice. Am J Pathol 2000, 157:1485-1493.
53. Marz P., Cheng J.G., Gadient R.A., Patterson P.H., Stoyan T., Otten U., et al. Sympathetic neurons can produce and respond to interleukin 6. Proc Natl Acad Sci U S A 1998, 95:3251-3256.
54. Marz P., Otten U., Rose-John S. Neural activities of IL-6-type cytokines often depend on soluble cytokine receptors. Eur J Neurosci 1999, 11:2995-3004.
55. Peters M., Muller A.M., Rose-John S. Interleukin-6 and soluble interleukin-6 receptor: direct stimulation of gp130 and hematopoiesis. Blood 1998, 92:3495-3504.
56. Schuster B., Kovaleva M., Sun Y., Regenhard P., Matthews V., Grötzinger J., et al. Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF. J Biol Chem 2003, 278:9528-9535.
57. Pflanz S., Timans J.C., Cheung J., Rosales R., Kanzler H., Gilbert J., et al. a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity 2002, 16:779-790.
58. Pflanz S., Hibbert L., Mattson J., Rosales R., Vaisberg E., Bazan J.F., et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J Immunol 2004, 172:2225-2231.
59. van Dam M., Mullberg J., Schooltink H., Stoyan T., Brakenhoff J.P., Graeve L., et al. Structure-function analysis of interleukin-6 utilizing human/murine chimeric molecules. Involvement of two separate domains in receptor binding. J Biol Chem 1993, 268:15285-15290.
60. van Snick J. Interleukin-6: an overview. Annu Rev Immunol 1990, 8:253-279.
61. Fattori E., Della Rocca C., Costa P., Giorgio M., Dente B., Pozzi L., et al. Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood 1994, 83:2570-2579.
62. Maione D., Di Carlo E., Li W., Musiani P., Modesti A., Peters M., et al. Coexpression of IL-6 and soluble IL-6R causes nodular regenerative hyperplasia and adenomas of the liver. EMBO J 1998, 17:5588-5597.
63. Grotzinger J., Kurapkat G., Wollmer A., Kalai M., Rose-John S. The family of the IL-6-type cytokines: specificity and promiscuity of the receptor complexes. Proteins 1997, 27:96-109.
64. Audet J., Miller C.L., Rose-John S., Piret J.M., Eaves C.J. Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic stem cells. Proc Natl Acad Sci U S A 2001, 98:1757-1762.
65. Hieronymus T., Gust T.C., Kirsch R.D., Jorgas T., Blendinger G., Goncharenko M., et al. Progressive and controlled development of mouse dendritic cells from Flt3+CD11b+ progenitors in vitro. J Immunol 2005, 174:2552-2562.
66. Sere K.M., Lin Q., Felker P., Rehage N., Klisch T., Ortseifer I., et al. Dendritic cell lineage commitment is instructed by distinct cytokine signals. Eur J Cell Biol 2012, 91:515-523.
67. Cressman D.E., Greenbaum L.E., DeAngelis R.A., Ciliberto G., Furth E.E., Poli V., et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 1996, 274:1379-1383.
68. Galun E., Zeira E., Pappo O., Peters M., Rose-John S. Liver regeneration induced by a designer human IL-6/sIL-6R fusion protein reverses severe hepatocellular injury. FASEB J 2000, 14:1979-1987.
69. Peters M., Blinn G., Jostock T., Schirmacher P., Meyer zum Buschenfelde K.H., Galle P.R., et al. Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration. Gastroenterology 2000, 119:1663-1671.
70. Hecht N., Pappo O., Shouval D., Rose-John S., Galun E., Axelrod J.H. Hyper-IL-6 gene therapy reverses fulminant hepatic failure. Mol Ther 2001, 3:683-687.
71. Mullberg J., Geib T., Jostock T., Hoischen S.H., Vollmer P., Voltz N., et al. IL-6 receptor independent stimulation of human gp130 by viral IL-6. J Immunol 2000, 164:4672-4677.
72. Adam N., Rabe B., Suthaus J., Grotzinger J., Rose-John S., Scheller J. Unraveling viral interleukin-6 binding to gp130 and activation of STAT-signaling pathways independently of the interleukin-6 receptor. J Virol 2009, 83:5117-5126.
73. Suthaus J., Adam N., Grotzinger J., Scheller J., Rose-John S. Viral interleukin-6. Structure, pathophysiology and strategies of neutralization. Eur J Cell Biol 2011, 90:495-504.
74. Suthaus J., Stuhlmann-Laeisz C., Tompkins V.S., Rosean T.R., Klapper W., Tosato G., et al. HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice. Blood 2012, 119:5173-5181.
75. Marz P., Heese K., Dimitriades-Schmutz B., Rose-John S., Otten U. Role of interleukin-6 and soluble IL-6 receptor in region-specific induction of astrocytic differentiation and neurotrophin expression. Glia 1999, 26:191-200.
76. Obreja O., Biasio W., Andratsch M., Lips K.S., Rathee P.K., Ludwig A., et al. Fast modulation of heat-activated ionic current by proinflammatory interleukin 6 in rat sensory neurons. Brain 2005, 128:1634-1641.
77. Atreya R., Mudter J., Finotto S., Mullberg J., Jostock T., Wirtz S., et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat Med 2000, 6:583-588.
78. Linker R.A., Luhder F., Kallen K.J., Lee D.H., Engelhardt B., Rose-John S., et al. IL-6 transsignalling modulates the early effector phase of EAE and targets the blood-brain barrier. J Neuroimmunol 2008, 205:64-72.
79. Scheller J., Chalaris A., Schmidt-Arras D., Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011, 1813:878-888.
80. Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci 2012, 8:1237-1247.
81. McFarland-Mancini M.M., Funk H.M., Paluch A.M., Zhou M., Giridhar P.V., Mercer C.A., et al. Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. J Immunol 2010, 184:7219-7228.
82. Ferreira R.C., Freitag D.F., Cutler A.J., Howson J.M., Rainbow D.B., Smyth D.J., et al. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genet 2013, 9:e1003444.
83. Okuda Y., Sakoda S., Bernard C.C., Fujimura H., Saeki Y., Kishimoto T., et al. IL-6-deficient mice are resistant to the induction of experimental autoimmune encephalomyelitis provoked by myelin oligodendrocyte glycoprotein. Int Immunol 1998, 10:703-708.
84. Serada S., Fujimoto M., Mihara M., Koike N., Ohsugi Y., Nomura S., et al. IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2008, 105:9041-9046.
85. Takagi M., Mihara M., Moriya Y., Nishimoto N., Yoshizaki K., Kishimoto T., et al. Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis. Arthritis Rheum 1998, 41:2117-2121.
86. Kallen K-J. The role of transsignalling via the agonistic soluble IL-6 receptor. Biochim Biophys Acta 2002, 1592:323-343.
87. Dimitrov S., Lange T., Benedict C., Scheller J., Rose-John S., Jones S., et al. Sleep enhances IL-6 trans-signaling in humans. FASEB J 2009, 23:3629-3636.
88. Rafiq S., Frayling T.M., Murray A., Hurst A., Stevens K., Weedon M.N., et al. A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects. Genes Immun 2007, 8:552-559.
89. Galicia J.C., Tai H., Komatsu Y., Shimada Y., Akazawa K., Yoshie H. Polymorphisms in the IL-6 receptor (IL-6R) gene: strong evidence that serum levels of soluble IL-6R are genetically influenced. Genes Immun 2004, 5:513-516.
90. Revez J.A., Bain L., Chapman B., Powell J.E., Jansen R., Duffy D.L., et al. A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk. Gens Immun 2013, 14(7):441-446.
91. Scheller J., Rose-John S. The interleukin 6 pathway and atherosclerosis. Lancet 2012, 380:338.
92. Nowell M.A., Richards P.J., Horiuchi S., Yamamoto N., Rose-John S., Topley N., et al. Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130. J Immunol 2003, 171:3202-3209.
93. Desgeorges A., Gabay C., Silacci P., Novick D., Roux-Lombard P., Grau G., et al. Concentrations and origins of soluble interleukin 6 receptor-alpha in serum and synovial fluid. J Rheumatol 1997, 24:1510-1516.
94. Zeni F., Tardy B., Vindimian M., Pain P., Gery P., Bertrand J.C. Soluble interleukin-6 receptor in patients with severe sepsis. J Infect Dis 1995, 172:607-608.
95. Kyrstsonis M.C., Dedoussis G., Baxevanis C., Stamatelou M., Maniatis A. Serum interleukin-6 (IL-6) and interleukin-4 (IL-4) in patients with multiple myeloma (MM). Br J Haematol 1996, 92:420-422.
96. Lavabre Bertrand T., Exbrayat C., Liautard J., Gaillard J.P., Baskevitch P.P., Poujol N., et al. Detection of membrane and soluble interleukin-6 receptor in lymphoid malignancies. Br J Haematol 1995, 91:871-877.
97. Doganci A., Eigenbrod T., Krug N., De Sanctis G.T., Hausding M., Erpenbeck V.J., et al. The IL-6R alpha chain controls lung CD4+CD4+CD25+T regulatory cell development and function during allergic airway inflammation in vivo. J Clin Invest 2005, 115:313-325.
98. Lo C.W., Chen M.W., Hsiao M., Wang S., Chen C.A., Hsiao S.M., et al. IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer. Cancer Res 2011, 71:424-434.
99. Rabe B., Chalaris A., May U., Waetzig G.H., Seegert D., Williams A.S., et al. Transgenic blockade of interleukin 6 transsignaling abrogates inflammation. Blood 2008, 111:1021-1028.
100. Zhang H., Neuhöfer P., Song L., Rabe B., Lesina M., Kurkowski M.U., et al. IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality. J Clin Invest 2013, 123:1019-1031.
101. Greenhill C.J., Rose-John S., Lissilaa R., Ferlin W., Ernst M., Hertzog P.J., et al. IL-6 trans-signaling modulates TLR4-dependent inflammatory responses via STAT3. J Immunol 2011, 186:1199-1208.
102. Barkhausen T., Tschernig T., Rosenstiel P., van Griensven M., Vonberg R.P., Dorsch M., et al. Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model. Crit Care Med 2011, 39:878-888.
103. Fattori E., Cappelletti M., Costa P., Sellitto C., Cantoni L., Carelli M., et al. Defective inflammatory response in interleukin 6-deficient mice. J Exp Med 1994, 180:1243-1250.
104. Xing Z., Gauldie J., Cox G., Baumann H., Jordana M., Lei X.F., et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 1998, 101:311-320.
105. Chen Q., Fisher D.T., Clancy K.A., Gauguet J-M.M., Wang W-C., Unger E., et al. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules through an IL-6 trans-signaling mechanism. Nat Immunol 2006, 7:1299-1308.
106. Appenheimer M.M., Girard R.A., Chen Q., Wang W.C., Bankert K.C., Hardison J., et al. Conservation of IL-6 trans-signaling mechanisms controlling l-selectin adhesion by fever-range thermal stress. Eur J Immunol 2007, 37:2856-2867.
107. Fisher D.T., Chen Q., Skitzki J.J., Muhitch J.B., Zhou L., Appenheimer M.M., et al. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J Clin Invest 2011, 121:3846-3859.
108. Teramo A., Gattazzo C., Passeri F., Lico A., Tasca G., Cabrelle A., et al. Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia. Blood 2013, 121:3843-3854.
109. Wang Y., van Boxel-Dezaire A.H., Cheon H., Yang J., Stark G.R. STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proc Natl Acad Sci U S A 2013, 110:16975-16980.
110. Wilke C.M., Bishop K., Fox D., Zou W. Deciphering the role of Th17 cells in human disease. Trends Immunol 2011, 32:603-611.
111. Dominitzki S., Fantini M.C., Neufert C., Nikolaev A., Galle P.R., Scheller J., et al. Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4+CD25T cells. J Immunol 2007, 179:2041-2045.
112. Jones G.W., McLoughlin R.M., Hammond V.J., Parker C.R., Williams J.D., Malhotra R., et al. Loss of CD4 T cell IL-6R expression during inflammation underlines a role for IL-6 trans-signaling in the local maintenance of Th17 cells. J Immunol 2010, 184:2130-2139.
113. Nowell M.A., Williams A.S., Carty S.A., Scheller J., Hayes A.J., Jones G.W., et al. Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis. J Immunol 2009, 182:613-622.
114. Grivennikov S., Karin E., Teric J., Mucida D., Yu G.Y., Vallabhapurapu S., et al. IL-6 and STAT3 are required for survival of intestinal epithelial cells and development of colitis associated cancer. Cancer Cell 2009, 15:103-113.
115. Becker C., Fantini M.C., Schramm C., Lehr H.A., Wirtz S., Nikolaev A., et al. TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 2004, 21:491-501.
116. Becker C., Fantini M.C., Wirtz S., Nikolaev A., Lehr H.A., Galle P.R., et al. IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle 2005, 4:217-220.
117. Matsumoto S., Hara T., Mitsuyama K., Yamamoto M., Tsuruta O., Sata M., et al. Essential roles of IL-6 trans-signaling in colonic epithelial cells, induced by the IL-6/soluble-IL-6 receptor derived from lamina propria macrophages, on the development of colitis-associated premalignant cancer in a murine model. J Immunol 2010, 184:1543-1551.
118. Schuett H., Oestreich R., Waetzig G.H., Annema W., Luchtefeld M., Hillmer A., et al. Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2012, 32:281-290.
119. Tsantikos E., Maxwell M.J., Putoczki T., Ernst M., Rose-John S., Tarlinton D.M., et al. Interleukin-6 trans-signaling exacerbates inflammation and renal pathology in lupus. Arthritis Rheum 2013, 65:2691-2702.
120. Lissilaa R., Buatois V., Magistrelli G., Williams A.S., Jones G.W., Herren S., et al. Although IL-6 trans-signaling is sufficient to drive local immune responses, classical IL-6 signaling is obligate for the induction of T cell-mediated autoimmunity. J Immunol 2010, 185:5512-5521.
121. Garbers C., Thaiss W., Jones G.W., Waetzig G.H., Lorenzen I., Guilhot F., et al. Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor. J Biol Chem 2011, 286:42959-42970.
122. Lang V.R., Englbrecht M., Rech J., Nusslein H., Manger K., Schuch F., et al. Risk of infections in rheumatoid arthritis patients treated with tocilizumab. Rheumatology 2012, 51:852-857.
123. Hoge J., Yan I., Janner N., Schumacher V., Chalaris A., Steinmetz O.M., et al. IL-6 controls the innate immune response against Listeria monocytogenes via classical IL-6 signaling. J Immunol 2013, 190:703-711.
124. Sodenkamp J., Waetzig G.H., Scheller J., Seegert D., Grotzinger J., Rose-John S., et al. Therapeutic targeting of interleukin-6 trans-signaling does not affect the outcome of experimental tuberculosis. Immunobiology 2012, 217:996-1004.
125. Rose-John S. Interleukin-6 biology is coordinated by membrane bound and soluble receptors. Acta Biochim Pol 2003, 50:603-611.
126. Lorenzen I., Shang W., Perbandt M., Petoukhov M.V., Svergun D.I., Waetzig G.H., et al. The structure of the unliganded extracellular domain of the interleukin-6 signal transducer gp130 in solution. Eur J Cell Biol 2011, 90:515-520.