Histamine Antagonizes Tumor Necrosis Factor (TNF) Signaling by Stimulating TNF Receptor Shedding from the Cell Surface and Golgi Storage Pool

Abstract

Tumor necrosis factor (TNF) activates pro-inflammatory functions of vascular endothelial cells (EC) through binding to receptor type 1 (TNFR1) molecules expressed on the cell surface. The majority of TNFR1 molecules are localized to the Golgi apparatus. Soluble forms of TNFR1 (as well as of TNFR2) can be shed from the EC surface and inhibit TNF actions. The relationships among cell surface, Golgi-associated, and shed forms of TNFR1 are unclear. Here we report that histamine causes transient loss of surface TNFR1, TNFR1 shedding, and mobilization of TNFR1 molecules from the Golgi in cultured human EC. The Golgi pool of TNFR1 serves both to replenish cell surface receptors and as a source of shed receptor. Histamine-induced shedding is blocked by TNF-α protease inhibitor, an inhibitor of TNF-α-converting enzyme, and through the H1 receptor via a MEK-1/p42 and p44 mitogen-activated protein kinase pathway. Cultured EC with histamine-induced surface receptor loss become transiently refractory to TNF. Histamine injection into human skin engrafted on immunodeficient mice similarly caused shedding of TNFR1 and diminished TNF-mediated induction of endothelial adhesion molecules. These results both clarify relationships among TNFR1 populations and reveal a novel anti-inflammatory activity of histamine. Tumor necrosis factor (TNF) activates pro-inflammatory functions of vascular endothelial cells (EC) through binding to receptor type 1 (TNFR1) molecules expressed on the cell surface. The majority of TNFR1 molecules are localized to the Golgi apparatus. Soluble forms of TNFR1 (as well as of TNFR2) can be shed from the EC surface and inhibit TNF actions. The relationships among cell surface, Golgi-associated, and shed forms of TNFR1 are unclear. Here we report that histamine causes transient loss of surface TNFR1, TNFR1 shedding, and mobilization of TNFR1 molecules from the Golgi in cultured human EC. The Golgi pool of TNFR1 serves both to replenish cell surface receptors and as a source of shed receptor. Histamine-induced shedding is blocked by TNF-α protease inhibitor, an inhibitor of TNF-α-converting enzyme, and through the H1 receptor via a MEK-1/p42 and p44 mitogen-activated protein kinase pathway. Cultured EC with histamine-induced surface receptor loss become transiently refractory to TNF. Histamine injection into human skin engrafted on immunodeficient mice similarly caused shedding of TNFR1 and diminished TNF-mediated induction of endothelial adhesion molecules. These results both clarify relationships among TNFR1 populations and reveal a novel anti-inflammatory activity of histamine. The immunological and inflammatory capacities of vascular endothelial cells (EC) 1The abbreviations used are: EC, endothelial cells; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; TACE, TNF-α-converting enzyme; MAP, mitogen-activated protein; MEK, MAP kinase/extracellular signal-regulated kinase kinase; PKC, protein kinase C; FACS, fluorescence-activated cell sorter; HUVEC, human umbilical vein EC; PMA, phorbol 12-myristate 13-acetate; PBS, phosphate-buffered saline; FCS, fetal calf serum; TBS, Tris-buffered saline; BSA, bovine serum albumin; RT, reverse transcriptase; gfp, green fluorescent protein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IKK, IκB kinase; ELISA, enzyme-linked immunosorbent assay; IL, interleukin; PIPES, 1,4-piperazinediethanesulfonic acid; CT, threshold cycle; LPR, late phase reaction; TAPI, TNF-α protease inhibitor; l-NMMA, NG-monomethyl-l-arginine. are activated in response to binding of homotrimeric TNF with cell surface receptors of 55 (TNFR1 or CD120a) or 75 (TNFR2 or CD 120b) kDa (1Madge L.A. Pober J.S. Exp. Mol. Pathol. 2001; 70: 317-325Crossref PubMed Scopus (263) Google Scholar). TNFR1 is the predominant receptor involved in new EC gene expression, although TNFR2 may increase the sensitivity of EC to TNF (2Slowik M.R. De Luca L.G. Fiers W. Pober J.S. Am. J. Pathol. 1993; 143: 1724-1730PubMed Google Scholar). New gene transcription results from activation of parallel signaling pathways involving several protein kinases, notably IκB kinase (IKK), various MAP kinases (including c-Jun N-terminal kinase, p42/44 MAP kinase and p38 MAP kinase), and protein kinase B (also known as Akt) (1Madge L.A. Pober J.S. Exp. Mol. Pathol. 2001; 70: 317-325Crossref PubMed Scopus (263) Google Scholar). IKK is central to the TNF activation response because this kinase uniquely phosphorylates IκB proteins, such as IκBα, triggering their degradation and thereby releasing sequestered transcription factor, NFκB (3Ledgerwood E.C. Pober J.S. Bradley J.R. Lab. Invest. 1999; 79: 1041-1050PubMed Google Scholar). NFκB is essential for the transcription of almost all of the pro-inflammatory gene products induced by TNF. IKK activation through TNFR1 is initiated by recruitment of the adaptor protein TNF receptor-associated death domain-containing protein to the cytoplasmic death domain of the ligand-occupied receptor molecule. Although the majority of TNFR1 molecules are located within the Golgi apparatus, TNF receptor-associated death domain associates with surface-expressed but not Golgi-associated receptors (4Bradley J.R. Thiru S. Pober J.S. Am. J. Pathol. 1995; 146: 27-32PubMed Google Scholar, 5Jones S.J. Ledgerwood E.C. Prins J.B. Galbraith J. Johnson D.R. Pober J.S. Bradley J.R. J. Immunol. 1999; 162: 1042-1048PubMed Google Scholar). The significance of the Golgi pool of TNFR1 molecules is unclear. One hypothesis is that it may act as a reservoir to increase surface receptor expression density, thereby sensitizing EC to the actions of TNF. There is precedence for this idea in smooth muscle cells, in which the TNF receptor family member Fas localizes predominantly to the Golgi, from where it can be translocated to the cell surface, thereby sensitizing cells to Fas ligand-induced killing (6Bennett M. Macdonald K. Chan S.W. Luzio J.P. Simari R. Weissberg P. Science. 1998; 282: 290-293Crossref PubMed Scopus (654) Google Scholar). Both types of TNF receptors can be released from the cell surface by the actions of a metalloproteinase called TNF-α-converting enzyme (TACE) (7Reddy P. Slack J.L. Davis R. Cerretti D.P. Kozlosky C.J. Blanton R.A. Shows D. Peschon J.J. Black R.A. J. Biol. Chem. 2000; 275: 14608-14614Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar). The shed extracellular domains of the receptors are soluble in water and are referred to as sTNFR1 or sTNFR2 (8Hooper N.M. Karran E.H. Turner A.J. Biochem. J. 1997; 321: 265-279Crossref PubMed Scopus (562) Google Scholar). Receptor shedding, which can reduce the surface expression of TNFR1 and TNFR2, may desensitize cells to TNF actions. Additionally, because TNFRs maintain their ability to bind ligand, they may serve as physiological neutralizing agents for TNF (9Van Zee K.J. Kohno T. Fischer E. Rock C.S. Moldawer L.L. Lowry S.F. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 4845-4849Crossref PubMed Scopus (785) Google Scholar, 10Hale K.K. Smith C.G. Baker S.L. Vanderslice R.W. Squires C.H. Gleason T.M. Tucker K.K. Kohno T. Russell D.A. Cytokine. 1995; 7: 26-38Crossref PubMed Scopus (102) Google Scholar), further dampening inflammatory responses. This idea is supported by the observation that patients with structural mutations in TNFR1 that prevent shedding by TACE are hypersensitive to TNF (11Galon J. Aksentijevich I. McDermott M.F. O'Shea J.J. Kastner D.L. Curr. Opin. Immunol. 2000; 12: 479-486Crossref PubMed Scopus (233) Google Scholar). Thus a second potential function of the Golgi pool of TNFR1 molecules is to serve as a reservoir for sTNFR1, reducing EC responses. TACE, which was initially identified as pro-inflammatory because of its role in TNF secretion (12Black R.A. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. Nelson N. Boiani N. Schooley K.A. Gerhart M. Davis R. Fitzner J.N. Johnson R.S. Paxton C.J. Cerretti D.P. 1997; PubMed Scopus Google Scholar, S.L. W. J.R. D. P. J. M. W. T. J.L. 1997; PubMed Scopus Google Scholar), may be or anti-inflammatory on it on an or releasing or that TACE activity in cells may be by several shedding in cell types can be initiated by phorbol a role for PKC, the of phorbol (7Reddy P. Slack J.L. Davis R. Cerretti D.P. Kozlosky C.J. Blanton R.A. Shows D. Peschon J.J. Black R.A. J. Biol. Chem. 2000; 275: 14608-14614Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar, M. T. J. Immunol. 1993; Google Scholar, A. J. Biochem. 1999; PubMed Scopus Google Scholar). of protein from cells, which is by TACE, is blocked by of the of and p44 MAP kinases J. K. N. S.L. J. 1997; PubMed Google Scholar). this may of that shedding from EC via a blocked by an inhibitor of p38 MAP kinase L.A. M.R. Pober J.S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). is are or of TACE in EC are Histamine is a released by activated human cells or that a but transient EC well of histamine are EC in loss of and of and EC of such as and U. 1997; PubMed Scopus Google Scholar). vascular and the and response of Histamine secretion of EC proteins, such as factor and surface of such as I. R. S. J. Invest. PubMed Scopus Google Scholar). Pober J.S. J. Immunol. Google that TNF histamine such as but not such as factor Histamine through receptors or and may protein kinase and MAP kinase activation A.J. J. 2001; PubMed Scopus Google Scholar). Histamine not IKK in EC and may inhibit activation of NFκB via of M. K. J. Biol. 1998; PubMed Scopus Google Scholar). the we the of histamine on TNFR1 expression in human EC. that this causes both mobilization of receptor from the Golgi pool and shedding of receptor into the This to H1 type receptors and is by a MEK-1/p42 and p44 MAP kinase pathway. These with transiently diminished TNF-mediated endothelial a new function for histamine and the that the Golgi receptor pool is a reservoir for both cell surface and shed TNFR1, TNFR2, and human TNFR1 and TNFR2 human TNF-α and human all from was from TACE and from and from and TNF-α protease inhibitor a inhibitor of TACE, was from inhibitor was from The was from and from and from all from umbilical vein EC from human umbilical and cultured in bovine fetal calf serum endothelial cell and in on as J.R. Thiru S. Pober J.S. Am. J. Pathol. 1995; Google Scholar). used are of by for of TNF Receptor by into cells and the cells with histamine for or EC with for an with histamine. cells a cell in with in PBS, and with on for and with for on EC and in of in cells by of Soluble by into as in and with histamine or for 1 or TAPI, the agents an of histamine or agents with histamine or the from well and for and the and for for sTNFR1 and sTNFR2 the and with and the results a an was and for to in in PBS, The was to a of in PBS, and the cells for The cells with and with for with histamine or for the and the cells protein inhibitor 1 and for for and the was to for 1 the and The or the in for and by as to in and with or histamine for various The shed receptors was and with or TNF or 1 was for the of of TAPI, was an histamine with and in protein inhibitor and 1 for and the and in for to by as was protein in by and to and S.J. Ledgerwood E.C. Prins J.B. Galbraith J. Johnson D.R. Pober J.S. Bradley J.R. J. Immunol. 1999; 162: 1042-1048PubMed Google Scholar). and used a of and by to the of for that the of was within the of or to on with of Golgi for and with or histamine or for 1 and EC by 1 of in to the 1 of in which the This and all for cells with PBS, EC by in for 1 and with PBS, with in PBS, for 1 with PBS, BSA, EC with for EC with PBS, and in PBS, and in in a TNFR1 green fluorescent protein into by transient to on with Johnson D.R. Pober J.S. Lab. Invest. 2000; PubMed Scopus Google a as K. W. Pober J.S. J. Exp. PubMed Scopus Google Scholar). and cells with or and or to histamine for the and a of Histamine on in of histamine on human skin immunodeficient mice engrafted with as P. J. P. Pober J.S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). human skin was from by the skin of and skin was engrafted a by the and and by the the of histamine on TNFR1 expression, with of histamine of histamine and histamine or of or and The was for the of TNF skin on was with of and the was with physiological to TNF mice and of TNF in the well from the and skin TNF in and for of skin was in of 1 in and by in T. Baker in for The was for and for as R.S. J. J.N. Thiru S. Pober J.S. Bradley J.R. Lab. Invest. 2001; PubMed Scopus Google Scholar). was in for 1 in in and for for and for The was with a of and the was by a of in on a and on for for in in to was and they with or in of and of or serum used as with TBS, the with with or in the for 1 a in TBS, with with for and in with and for in a an of the of TNFR1, in on a of a to the was for was from skin as skin was into 1 of and a further to the and by of the for to was further a with a was of the used as to of and in a was the and in as J. K.J. PubMed Scopus Google Scholar). a of and and into of and as to a of for and of for and for 1 the phase of was by of fluorescent of by activity of increase in is to the of and the which the a is the a and to for and is not by TNF and was used as an gene to for was to for from of for and and by the are as and from of with as the the and as the the significance of was by of the of Histamine on TNF Receptor and cultured TNFR2 and to a TNFR1 on their cell surface (2Slowik M.R. De Luca L.G. Fiers W. Pober J.S. Am. J. Pathol. 1993; 143: 1724-1730PubMed Google Scholar). of EC with histamine for cell surface expression of both receptors as by The of TNFR1 on the cell surface to by 1 the of TNFR2 was transiently endothelial cell surface TNF receptor of are to are are are are are to are in a new with its of surface receptor expression, histamine induced an increase in soluble TNFR1 and TNFR2 shed into the Receptor shedding was the of histamine this histamine-induced shedding of TNFR1 was and by the histamine H1 receptor but not by the results for shedding of TNFR2, although the shed was that on the surface was caused by receptor shedding in a through its H1 in a new of TACE in Histamine-induced to both TNF receptors from the cell surface, and it was that receptor shedding induced by be by the TACE inhibitor (7Reddy P. Slack J.L. Davis R. Cerretti D.P. Kozlosky C.J. Blanton R.A. Shows D. Peschon J.J. Black R.A. J. Biol. Chem. 2000; 275: 14608-14614Abstract Full Text Full Text PDF PubMed Scopus (443) Google histamine-induced shedding TACE, we with for by the cell surface of both TNFR1 and TNFR2, with a of shedding the shedding caused by histamine. the of TNFR1 on the cell surface induced by histamine further the receptor loss and These results that histamine receptor loss through shedding, although it is that may be of on the histamine-induced of TNF receptor cell surface expression and histamine-induced shedding of TNF on the cell in to blocked the shedding of sTNFR1 into induced by histamine. sTNFR1 with was and this increase was cells with and to blocked the shedding of sTNFR1 into induced by histamine. sTNFR1 with was and this increase was cells with and to blocked the shedding of sTNFR1 into induced by histamine. sTNFR1 with was and this increase was cells with and in a new The of TACE in the histamine response to TACE expression and in EC. TACE protein was in both and of TACE in forms with of and which to the and the enzyme, as J. Biochem. J. 2000; PubMed Scopus Google in human cell Both forms of the enzyme in surface TACE was as the Although cell surface TACE in cells J.R. Black R.A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), the expression of the and the in endothelial cell was not by histamine or These that TACE is expressed in but not a in which TACE activation by histamine is by to the of on TNF Receptor observation that endothelial cells TNFR2 TNFR1 on their surface (4Bradley J.R. Thiru S. Pober J.S. Am. J. Pathol. 1995; 146: 27-32PubMed Google Scholar), of TNFR1 into the in response to the that TNFR1 molecules may to the shed receptor TNFR1 to the of shed receptor. is a that can protein from the Golgi to the Full Text PDF PubMed Scopus Google Scholar). 1 not the of TNFR1 shed into the but the cell surface was This that mobilization of TNFR1 from an was to maintain the cell surface of the receptor. TNFR2 that of this receptor on the cell surface on mobilization from an the of soluble receptors shed into the in response to histamine This that histamine-induced shedding mobilization of receptor shedding caused by sTNFR1 with was and was by with of on the histamine-induced of TNF receptor cell surface expression, and histamine-induced shedding of TNF on the cell in with with with with with with with in a new The Golgi pool the majority of TNFR1 molecules in EC. histamine TNFR1 from the Golgi apparatus, we the of TNFR1 in and cells by TNFR1 with a Golgi in cells with histamine TNFR1 from the Golgi to a the a but the results in and cells, we with protein and we used cells to of the receptor in in cells localized to the with receptor in the Golgi apparatus. of the cells to histamine to a of the receptor from the the to loss of from the These results are with in and cells, as well as with the results of and and that histamine causes a of the receptor from the Golgi to the surface and into the of by the signaling by which histamine activates TACE and causes shedding of the of several agents Histamine activates in EC via can soluble and protein kinase The inhibitor not shedding caused by histamine or Histamine can protein kinase in EC. S. J. 2000; PubMed Scopus Google Scholar), a protein kinase inhibitor, shedding caused by in a but on the shedding caused by histamine the shedding of which is by TACE, J. K. N. S.L. J. 1997; PubMed Google Scholar), we this as The inhibitor shedding caused by histamine as well as the inhibitor of the p38 mitogen-activated protein kinase MAP kinase), not or histamine-induced shedding These results are with the hypothesis that MAP kinase is involved in TACE activation in EC but that the activation of this by histamine is of of Histamine-induced in TNF on TNF the shedding of TNFR1 caused by histamine on TNF in HUVEC, degradation of was by its histamine on the of from to TNF, as (1Madge L.A. Pober J.S. Exp. Mol. Pathol. 2001; 70: 317-325Crossref PubMed Scopus (263) Google Scholar), induced degradation with histamine for an to of TNF diminished the of the of histamine The of to the of the in the cell surface of TNFR1 the shedding of TNFR1 induced by histamine with the of histamine on degradation degradation in HUVEC, but are not to the of the histamine cells for histamine with These that the of histamine on TNF in can be to the shedding of cell surface is that cell surface receptor loss of by is for the because the shed receptors was TNF and the of histamine was TNF was the not The of neutralizing in the can be by the of receptors that are to to TNF, which are for sTNFR1 and for sTNFR2 (9Van Zee K.J. Kohno T. Fischer E. Rock C.S. Moldawer L.L. Lowry S.F. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 4845-4849Crossref PubMed Scopus (785) Google Scholar). The of in histamine of Histamine on TNF and TNF in the results with cultured in we used a involving of human skin immunodeficient we with or histamine and the by TNFR1 molecules in the with with histamine injection caused a of human TNFR1 in and cell of in the of was not of TNFR1 by in of TNFR1 within EC was but the of not the of histamine on TNF in we used to and is in its expression to EC is expressed by EC the Although can EC are the predominant cell types that to TNF. of TNF a increase in both and with histamine in of TNF induction of both and Histamine is a of the that of with molecules on the surface of cells and vascular endothelial cells are for the actions of histamine. within of and are several by a late phase by and TNF is to be an of the skin TNF from cells in the skin to expression of in Pober J.S. R.S. J. Invest. PubMed Scopus Google Scholar), and in a of TNF to recruitment of J.R. S.J. J. Invest. PubMed Scopus Google Scholar). TNF is of the involved in the recruitment of in the A. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). cells of TNF that can be released into the extracellular on J.R. S.J. PubMed Scopus Google Scholar, D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). cells a source for the of both histamine and TNF of and the actions of TNF are to be for the of an results that in this actions of histamine may TNF actions through on TNF receptor Histamine both TNFR1 and TNFR2 on the cell surface of endothelial cells by receptor TACE can both TNF receptors from the cell surface, and we that TACE is expressed in EC. Histamine to shedding through activation of TACE, as its be blocked by the TACE inhibitor but not metalloproteinase which is the for TACE P. R. R. S. P. J. Immunol. 2000; PubMed Scopus Google Scholar). Although TNFR2 is the predominant endothelial cell surface TNF receptor (4Bradley J.R. Thiru S. Pober J.S. Am. J. Pathol. 1995; 146: 27-32PubMed Google Scholar), of TNFR1 released into the in response to the that TNFR1 was from the Golgi This idea is supported by the observation that the Golgi and histamine-induced receptor shedding, and by observation of the mobilization of receptor in response to histamine. EC shedding of TNFR1 is by the expression of of TNFR1 shedding a protein that to the extracellular domain of TNFR1, and shedding of TNFR1 but not TNFR2 S. M. W. D. S.J. J. Invest. PubMed Scopus Google Scholar). Histamine shedding of both TNFR1 and TNFR2, that its is not be by a on but expression of in EC to the shedding of of TNFR1 was by both and and shedding of TNFR1 be by a inhibitor, the observation that TACE can be activated by protein kinase A. J. Biochem. 1999; PubMed Scopus Google Scholar). results that histamine through a pathway. that protein shedding is by a that can be activated by and second in both a and 2000; PubMed Scopus Google Scholar, P. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). induced by histamine was blocked by a inhibitor which of the shedding induced by histamine was initiated through a pathway. that was not to be to TACE P. D. J.L. J.R. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). shedding induced by or histamine was not by the l-NMMA, although it is that which can TACE P. J.R. J. J. 2001; PubMed Scopus (233) Google Scholar), may be may be several to activation of TACE and shedding of cell surface and signaling pathways may be activated by A. J. Biochem. 1999; PubMed Scopus Google Scholar, J. J. J. Biol. 1995; PubMed Scopus Google Scholar). that histamine TNF through a on TNF receptor The of histamine on both TNFR1 cell surface expression and degradation was with both the This is with the report that TNF degradation predominantly through TNFR1 Tucker S.J. P. 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PubMed Scopus Google and can act in in to the binding and in the response to histamine is vascular and recruitment of a of histamine on TNF but a of histamine on EC to TNF in cultured cells the of histamine on TNF to be through loss of cell surface receptors an of shed soluble of TNF by shed receptors may to loss of EC to TNF in histamine of human that may be a source of in this Histamine caused a of extracellular TNFR1 in human skin engrafted mice and diminished of the endothelial gene in response to TNF. The predominant cell which of TNFR1 mobilization and shedding in engrafted although mobilization of TNFR1 in EC. Soluble TNF receptors are as of inflammatory Soluble TNF receptor in of and a soluble as an anti-inflammatory (11Galon J. Aksentijevich I. McDermott M.F. O'Shea J.J. Kastner D.L. Curr. Opin. Immunol. 2000; 12: 479-486Crossref PubMed Scopus (233) Google Scholar). EC are the cell type TNFR1 R.S. J. J.N. Thiru S. Pober J.S. Bradley J.R. Lab. Invest. 2001; PubMed Scopus Google Scholar), and EC as a source of The role for soluble TNFR1 as a physiological inhibitor of inflammatory is supported by the observation that patients with mutations in the gene TNFR1, which extracellular and and shedding of the receptor a known as receptor-associated This is by of skin I. J. M. E. K. R. J. A.J. M. O'Shea J.J. Kastner D.L. Am. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the of histamine on mobilization of Golgi-associated TNFR1 and receptor shedding both the relationships among cell surface, Golgi-associated, and shed TNFR1 molecules and a novel through which histamine may the of TNF to an inflammatory response in an to EC as a source of sTNFR1 and that the Golgi pool of TNFR1 molecules may serve as an pool of anti-inflammatory