Abstract
Endothelial cells initiate the inflammatory response by recruiting and activating leukocytes. IL-6 is not an agonist for this, but we found soluble IL-6 receptor alpha-subunit (IL-6Ralpha), with their constitutive IL-6 synthesis, stimulated endothelial cells to synthesize E-selectin, intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, IL-6, and IL-8, and to bind neutrophils. Neutrophils express significant amounts of IL-6Ralpha and upon stimulation shed it: this material activates endothelial cells through a newly constituted IL-6 receptor. Retrograde signaling from PMN activated in the extravascular compartment to surrounding endothelial cells will recruit more and a wider variety of leukocytes. The limiting signal is a soluble receptor, not a cytokine.
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- Biffl W. L., Moore E. E., Moore F. A., Barnett C. C., Jr, Silliman C. C., Peterson V. M. Interleukin-6 stimulates neutrophil production of platelet-activating factor. J Leukoc Biol. 1996 Apr;59(4):569–574. doi: 10.1002/jlb.59.4.569. [DOI] [PubMed] [Google Scholar]
- Brown T. J., Rowe J. M., Liu J. W., Shoyab M. Regulation of IL-6 expression by oncostatin M. J Immunol. 1991 Oct 1;147(7):2175–2180. [PubMed] [Google Scholar]
- Cassatella M. A. The production of cytokines by polymorphonuclear neutrophils. Immunol Today. 1995 Jan;16(1):21–26. doi: 10.1016/0167-5699(95)80066-2. [DOI] [PubMed] [Google Scholar]
- Desgeorges A., Gabay C., Silacci P., Novick D., Roux-Lombard P., Grau G., Dayer J. M., Vischer T., Guerne P. A. Concentrations and origins of soluble interleukin 6 receptor-alpha in serum and synovial fluid. J Rheumatol. 1997 Aug;24(8):1510–1516. [PubMed] [Google Scholar]
- Economides A. N., Ravetch J. V., Yancopoulos G. D., Stahl N. Designer cytokines: targeting actions to cells of choice. Science. 1995 Nov 24;270(5240):1351–1353. doi: 10.1126/science.270.5240.1351. [DOI] [PubMed] [Google Scholar]
- Ekida T., Nishimura C., Masuda S., Itoh S., Shimada I., Arata Y. A receptor-binding peptide from human interleukin-6: isolation and a proton nuclear magnetic resonance study. Biochem Biophys Res Commun. 1992 Nov 30;189(1):211–220. doi: 10.1016/0006-291x(92)91546-3. [DOI] [PubMed] [Google Scholar]
- Hibi M., Murakami M., Saito M., Hirano T., Taga T., Kishimoto T. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990 Dec 21;63(6):1149–1157. doi: 10.1016/0092-8674(90)90411-7. [DOI] [PubMed] [Google Scholar]
- Honda M., Yamamoto S., Cheng M., Yasukawa K., Suzuki H., Saito T., Osugi Y., Tokunaga T., Kishimoto T. Human soluble IL-6 receptor: its detection and enhanced release by HIV infection. J Immunol. 1992 Apr 1;148(7):2175–2180. [PubMed] [Google Scholar]
- Hooper W. C., Phillips D. J., Evatt B. L. Endothelial cell protein S synthesis is upregulated by the complex of IL-6 and soluble IL-6 receptor. Thromb Haemost. 1997 May;77(5):1014–1019. [PubMed] [Google Scholar]
- Horiuchi S., Koyanagi Y., Zhou Y., Miyamoto H., Tanaka Y., Waki M., Matsumoto A., Yamamoto M., Yamamoto N. Soluble interleukin-6 receptors released from T cell or granulocyte/macrophage cell lines and human peripheral blood mononuclear cells are generated through an alternative splicing mechanism. Eur J Immunol. 1994 Aug;24(8):1945–1948. doi: 10.1002/eji.1830240837. [DOI] [PubMed] [Google Scholar]
- Kishimoto T. K., Jutila M. A., Berg E. L., Butcher E. C. Neutrophil Mac-1 and MEL-14 adhesion proteins inversely regulated by chemotactic factors. Science. 1989 Sep 15;245(4923):1238–1241. doi: 10.1126/science.2551036. [DOI] [PubMed] [Google Scholar]
- Kukielka G. L., Smith C. W., Manning A. M., Youker K. A., Michael L. H., Entman M. L. Induction of interleukin-6 synthesis in the myocardium. Potential role in postreperfusion inflammatory injury. Circulation. 1995 Oct 1;92(7):1866–1875. doi: 10.1161/01.cir.92.7.1866. [DOI] [PubMed] [Google Scholar]
- Kurose I., Argenbright L. W., Wolf R., Granger D. N. Oxidative stress during platelet-activating factor-induced microvascular dysfunction. Microcirculation. 1996 Dec;3(4):401–410. doi: 10.3109/10739689609148313. [DOI] [PubMed] [Google Scholar]
- Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
- Lewis M. S., Whatley R. E., Cain P., McIntyre T. M., Prescott S. M., Zimmerman G. A. Hydrogen peroxide stimulates the synthesis of platelet-activating factor by endothelium and induces endothelial cell-dependent neutrophil adhesion. J Clin Invest. 1988 Dec;82(6):2045–2055. doi: 10.1172/JCI113825. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lorant D. E., McEver R. P., McIntyre T. M., Moore K. L., Prescott S. M., Zimmerman G. A. Activation of polymorphonuclear leukocytes reduces their adhesion to P-selectin and causes redistribution of ligands for P-selectin on their surfaces. J Clin Invest. 1995 Jul;96(1):171–182. doi: 10.1172/JCI118018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Modur V., Feldhaus M. J., Weyrich A. S., Jicha D. L., Prescott S. M., Zimmerman G. A., McIntyre T. M. Oncostatin M is a proinflammatory mediator. In vivo effects correlate with endothelial cell expression of inflammatory cytokines and adhesion molecules. J Clin Invest. 1997 Jul 1;100(1):158–168. doi: 10.1172/JCI119508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Modur V., Zimmerman G. A., Prescott S. M., McIntyre T. M. Endothelial cell inflammatory responses to tumor necrosis factor alpha. Ceramide-dependent and -independent mitogen-activated protein kinase cascades. J Biol Chem. 1996 May 31;271(22):13094–13102. doi: 10.1074/jbc.271.22.13094. [DOI] [PubMed] [Google Scholar]
- Mosley B., De Imus C., Friend D., Boiani N., Thoma B., Park L. S., Cosman D. Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation. J Biol Chem. 1996 Dec 20;271(51):32635–32643. doi: 10.1074/jbc.271.51.32635. [DOI] [PubMed] [Google Scholar]
- Mullen P. G., Windsor A. C., Walsh C. J., Fowler A. A., 3rd, Sugerman H. J. Tumor necrosis factor-alpha and interleukin-6 selectively regulate neutrophil function in vitro. J Surg Res. 1995 Feb;58(2):124–130. doi: 10.1006/jsre.1995.1020. [DOI] [PubMed] [Google Scholar]
- Müllberg J., Dittrich E., Graeve L., Gerhartz C., Yasukawa K., Taga T., Kishimoto T., Heinrich P. C., Rose-John S. Differential shedding of the two subunits of the interleukin-6 receptor. FEBS Lett. 1993 Oct 11;332(1-2):174–178. doi: 10.1016/0014-5793(93)80507-q. [DOI] [PubMed] [Google Scholar]
- Müllberg J., Durie F. H., Otten-Evans C., Alderson M. R., Rose-John S., Cosman D., Black R. A., Mohler K. M. A metalloprotease inhibitor blocks shedding of the IL-6 receptor and the p60 TNF receptor. J Immunol. 1995 Dec 1;155(11):5198–5205. [PubMed] [Google Scholar]
- Müllberg J., Schooltink H., Stoyan T., Günther M., Graeve L., Buse G., Mackiewicz A., Heinrich P. C., Rose-John S. The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol. 1993 Feb;23(2):473–480. doi: 10.1002/eji.1830230226. [DOI] [PubMed] [Google Scholar]
- Müllberg J., Schooltink H., Stoyan T., Günther M., Graeve L., Buse G., Mackiewicz A., Heinrich P. C., Rose-John S. The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol. 1993 Feb;23(2):473–480. doi: 10.1002/eji.1830230226. [DOI] [PubMed] [Google Scholar]
- Peters M., Jacobs S., Ehlers M., Vollmer P., Müllberg J., Wolf E., Brem G., Meyer zum Büschenfelde K. H., Rose-John S. 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 Apr 1;183(4):1399–1406. doi: 10.1084/jem.183.4.1399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Peters M., Odenthal M., Schirmacher P., Blessing M., Fattori E., Ciliberto G., Meyer zum Buschenfelde K. H., Rose-John S. Soluble IL-6 receptor leads to a paracrine modulation of the IL-6-induced hepatic acute phase response in double transgenic mice. J Immunol. 1997 Aug 1;159(3):1474–1481. [PubMed] [Google Scholar]
- Porteu F., Nathan C. Shedding of tumor necrosis factor receptors by activated human neutrophils. J Exp Med. 1990 Aug 1;172(2):599–607. doi: 10.1084/jem.172.2.599. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Romano M., Sironi M., Toniatti C., Polentarutti N., Fruscella P., Ghezzi P., Faggioni R., Luini W., van Hinsbergh V., Sozzani S. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity. 1997 Mar;6(3):315–325. doi: 10.1016/s1074-7613(00)80334-9. [DOI] [PubMed] [Google Scholar]
- Smiley P. L., Stremler K. E., Prescott S. M., Zimmerman G. A., McIntyre T. M. Oxidatively fragmented phosphatidylcholines activate human neutrophils through the receptor for platelet-activating factor. J Biol Chem. 1991 Jun 15;266(17):11104–11110. [PubMed] [Google Scholar]
- Tedder T. F. Cell-surface receptor shedding: a means of regulating function. Am J Respir Cell Mol Biol. 1991 Oct;5(4):305–306. doi: 10.1165/ajrcmb/5.4.305. [DOI] [PubMed] [Google Scholar]
- 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 Sep;64(9):3646–3651. doi: 10.1128/iai.64.9.3646-3651.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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 Jul 23;93(15):7882–7887. doi: 10.1073/pnas.93.15.7882. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Watson C., Whittaker S., Smith N., Vora A. J., Dumonde D. C., Brown K. A. IL-6 acts on endothelial cells to preferentially increase their adherence for lymphocytes. Clin Exp Immunol. 1996 Jul;105(1):112–119. doi: 10.1046/j.1365-2249.1996.d01-717.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yee J., Giannias B., Kapadia B., Chartrand L., Christou N. V. Exudative neutrophils. Modulation of microbicidal function in the inflammatory microenvironment. Arch Surg. 1994 Jan;129(1):99–105. doi: 10.1001/archsurg.1994.01420250111014. [DOI] [PubMed] [Google Scholar]
- 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 Aug;172(2):607–608. doi: 10.1093/infdis/172.2.607. [DOI] [PubMed] [Google Scholar]
- Zimmerli W., Seligmann B., Gallin J. I. Exudation primes human and guinea pig neutrophils for subsequent responsiveness to the chemotactic peptide N-formylmethionylleucylphenylalanine and increases complement component C3bi receptor expression. J Clin Invest. 1986 Mar;77(3):925–933. doi: 10.1172/JCI112391. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zimmerman G. A., McIntyre T. M. Neutrophil adherence to human endothelium in vitro occurs by CDw18 (Mo1, MAC-1/LFA-1/GP 150,95) glycoprotein-dependent and -independent mechanisms. J Clin Invest. 1988 Feb;81(2):531–537. doi: 10.1172/JCI113351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zimmerman G. A., McIntyre T. M., Prescott S. M. Adhesion and signaling in vascular cell--cell interactions. J Clin Invest. 1996 Oct 15;98(8):1699–1702. doi: 10.1172/JCI118967. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zimmerman G. A., McIntyre T. M., Prescott S. M. Thrombin stimulates the adherence of neutrophils to human endothelial cells in vitro. J Clin Invest. 1985 Dec;76(6):2235–2246. doi: 10.1172/JCI112232. [DOI] [PMC free article] [PubMed] [Google Scholar]