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Evidence for Both Histamine H1 and H2 Receptors on Human Articular Chondrocytes

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Evidence for Both Histamine H1 and H2 Receptors on Human Articular Chondrocytes Ann Rheum Dis: first published as 10.1136/ard.46.6.431 on 1 June 1987. Downloaded from Annals of the Rheumatic Diseases, 1987; 46, 431-435 Evidence for both histamine H1 and H2 receptors on human articular chondrocytes D J TAYLOR AND D E WOOLLEY From the University Department of Medicine, University Hospital of South Manchester, West Didsbury, Manchester, UK SUMMARY Using specific histamine HI and H2 receptor antagonists, evidence is presented for the existence of both H1 and H2 receptors on human articular chondrocytes in vitro. Stimulation of the H1 receptor by histamine (range 0-18 to 17-8 imol/l) significantly increased prostaglandin E (PGE) production, while activation of the histamine H2 receptor increased intracellular cyclic adenosine-5'-monophosphate (AMP). The histamine H1 antagonists mepyramine and tripelen- namine blocked the histamine induced increase in PGE production, and the H2 antagonists cimetidine and ranitidine prevented the increase in intracellular cyclic AMP. These observations suggest that mast cell-chondrocyte interactions mediated via histamine may contribute to some of the pathophysiological changes observed in joint disease. Key words: adenosine cyclic monophosphate, prostaglandins E. copyright. After our observation of mast cells at sites of was shown to be mediated not by a histamine H2 cartilage erosion in rheumatoid knee joints' we have receptor but by a type 1 receptor. examined the potential of mast cell components to affect chondrocyte metabolism. The addition of Materials and methods http://ard.bmj.com/ whole mast cell products, prepared from purified rat or dog mast cells, caused a marked increase in the Materials were obtained from the sources previously intracellular cyclic AMP levels of cultured chondro- given,2 with the addition of the following [3H]PGE2 cytes, an observation subsequently explained by the was obtained from Amersham International, Amer- demonstration of histamine H2 receptors on chon- sham, Bucks, UK; anti-PGE serum was obtained drocytes derived from human, canine, and fetal from Miles Laboratories Limited, Slough, UK; bovine articular cartilage.2 As with histamine H2 recombinant murine interleukin 1 (ILl) was a gift receptors found in gastric mucosa, rat uterus, and from Roche Products Ltd, Welwyn Garden City, on September 27, 2021 by guest. Protected guinea pig heart,3 stimulation by histamine activated Herts and was prepared as previously described.6 adenylate cyclase and produced an increase in (One unit of ILl activity induces 50% maximal intracellular cyclic AMP. Alterations in intracellular proliferative response in the thymocyte costimulation cyclic AMP levels have been shown to affect a assay.) number of cellular processes, including prostaglan- din (PG) production by human adipose tissue.5 CELL CULTURE Since increased PG production is a common feature Human articular chondrocytes (HAC) were obtained of inflammatory joint disease we have investigated by proteolytic digestion of macroscopically normal the effect of histamine on PGE production by articular cartilage from femoral heads and condyles chondrocytes. We report here that histamine was obtained from remedial surgery as previously de- found to increase PGE production by human scribed.7 The cells were grown in Dulbecco's modi- articular chondrocytes, but surprisingly this process fled Eagle's medium (DMEM) with 10% (v/v) fetal calf serum supplemented with penicillin, strepto- Accepted for publication 8 January 1987. and Correspondence to Dr D J Taylor, University Department of mycin fungizone. Cultures were incubated at Medicine, University Hospital of South Manchester, West Didsbury, 37°C in CO2/air 1:19 in a water saturated atmosphere Manchester M20 8LR, UK. and when confluent subcultured using conventional 431 Ann Rheum Dis: first published as 10.1136/ard.46.6.431 on 1 June 1987. Downloaded from 432 Taylor, Woolley trypsin treatment and replating at reduced density. further 10 min at 4°C. After centrifugation at 1500 g The chondrocyte cultures used in these experiments for 10 min at 4°C the supernatant was decanted and were from primary and passaged cells, both of which counted in a liquid scintillation spectrometer con- were qualitatively similar in their response to nected to a Beckman DP5500 curve-fit processor. histamine. The sensitivity of the assay was 5 pg when deter- mined by two standard deviations at zero dose. CYCL IC AMP STUDIES For measurement of intracellular cyclic AMP the [-H]MEPYRAMINE BINDING STUDIES chondrocytes were incubated in DMEM containing Radioligand binding studies were performed on 800 itmol/l isobutyl-L-methylxanthine (IBMX) with confluent monolayers of chondrocytes using the and without histamine and antagonists for five method recently described for rheumatoid synovial minutes at 37°C. After removal of the incubation cells.14 After a 90 min incubation at 0-40C with medium the cells were precipitated with 6% (w/v) 10 nM [3H]mepyramine the medium was removed HCl04 and processed for cyclic AMP determination and the cells were rapidly rinsed with buffer before as described previously.8 The cyclic AMP was detaching by incubation at 37°C with 0-25% (w/v) measured by a competitive protein binding assay trypsin. The cells were transferred quantitatively to using the binder isolated from bovine adrenal vials for liquid scintillation counting. All treatments glands.9 were performed in duplicate or triplicate. PGE STUDIE,S Results To examine the effect of histamine on PGE produc- HISTAMINE EFFECTS ON PGE PRODUCTION tion chondrocytes were preincubated for between 16 Histamine stimulated PGE production by HAC in a and 24 hours with 10 or 20% (v/v) synovial factor (SF), which has previously been to stimu- reported PGE late chondrocytic PG production.' This overcame Table I Histaminie stimullation of chondrocYte copyright. the problem of very low basal PGE production, production which was normally at the limit of assay sensitivity. Treaotneot P(E (ng/well1/h) SF was the medium removed after three days from a primary culture of adherent rheumatoid synovial DMEM 2^20 (0(08);), cells, known to be a good source of interleukin 1,11 Histamine (()- 18 tmou/l) 2 79 (0109)* hiistaminc (1 8 fimol/l) 464 (() 11)* and after centrifugation to remove cellular debris Histaminc (17-8 ltmol/1) 5 24 (0(09)* was used without further treatment. Cells were also +Mcpsraminc (143 timol/1) 2 17 (0.05) http://ard.bmj.com/ preincubated for 20 hours with 16 units/ml murine +Cimctidinc (4(0 umol/) 4-30 (0-20)* ILI, which like SF markedly stimulated chondrocyte The chondrocvtes were prcincubatcd for 24 h with 20 (XIs) SF. prostaglandin E production. After removing the Thc activating mcdium was rcmovcd and the cclls wcrc washed activating medium the cells were washed three times with HiBSS bcforc adding histaminc and its antagonists for onc with Hanks's balanced salt solution (HBSS) and hour. DMEM was added with or without histamine and its :p<()-()|I. antagonists. This second incubation was for either ,Valucs (irc the mcan (SEM). n=4. on September 27, 2021 by guest. Protected one or two hours, after which the medium was Table 2 Histanminle stimtulatiotn of PGE produictiotn front removed for PGE measurement. The inclusion of chonidrocvtes preiticlbhated with SF or mnurinie ILI indomethacin (14 [tmol/l) reduced PGE production to non-detectable levels, which confirmed that PGE Freattient1t 'GE (Oigl'we/Ilh obtained during the histamine incubation represented new synthesis and not leakage of preformed material. SF activated I lI (activiated PGE was measured in culture media by 6-13 (0.) ; (1185) 12 DMEM 12(08 radioimmunoassay using an antiserum with similar Histaminc (4.5 umol/1) 15X81 ((097)'' 23.57 ( 2'09):' specificity towards the prostaglandins El and E2 and +Mcpyramine (0-5 pmol/1) 5-69 (-164) 14 76 (1)46) charcoal to bound +Tripeclennamine (0-5 ItmolI/) 4-75 ((1-2t9) 8 21 (05-7) using dextran coated separate +Cimctidinc(79 rmolIl) 1174 (1)-51) 188-1 (()89)* from free fractions.13 The antiserum was diluted in +Ranitidinc (6.3 umonlI) 14,-21 ((138)* 20-83 (2 64)' assay buffer (50 mM phosphate, 0 15 M NaCl, 0 1% (w/v) bovine serum albumin, and 0-05% (w/v) The chondroctes were prcincubated for 20) h with cithci 1)0 (x/v) at and 100 was added to the SF or 16 units/ml murine ILI. The activating mcdium wias rcmoxcd sodium azide pH 7.4) [tl and the cclls werc washcd with HBSS before adding histatminc and same volume of sample and [3HIPGE2. After 90 min its antaigonists for onc hour. at 4°C 1 mg of dextran coated charcoal was added to "Valucs significantlv incrcased abovc control at p<()-(l2. each tube, which after vortexing was incubated for a Valucs ,re thenmcan (SEM). n=3. Ann Rheum Dis: first published as 10.1136/ard.46.6.431 on 1 June 1987. Downloaded from Histamine receptors on human chondrocytes 433 concentration related manner, with concentrations 6-o as low as 0-18 .mollI causing a significant increase above control (Table 1). In four preparations of C HAC, histamine (17.8 ,umol/l) increased PGE pro- .iI.. 5- duction by an average of 5.4 (range 2*3-11-3) times 0. on 4- that of the control. The stimulation was prevented E \0 by the receptor antagonists mepyramine and CV) HI o 3- tripelennamine, was not significantly reduced by a x 10-fold higher concentration of the H2 antagonist 1- ranitidine, and only slightly reduced by cimetidine c 2- (Tables 1 and 2). l- 0 The H1 antagonists chlorpheniramine, mepy- a-I ramine, and tripelennamine each caused a dose C. A~\u related inhibition of the histamine stimulated PGE production at concentrations below 10-6 mol/l (Fig. 2 1). When added without histamine the highest -log I [CNorpheniramine] (mol/l) concentration of histamine antagonists used in these experiments did not significantly change the control Fig.
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