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Activation by Inhibition of Second Messenger Compounds 1230 Annals ofthe Rheumatic Diseases 1992; 51: 1230-1236 Sulphasalazine inhibition of human granulocyte Ann Rheum Dis: first published as 10.1136/ard.51.11.1230 on 1 November 1992. Downloaded from activation by inhibition of second messenger compounds Gunnar Carlin, Richard Djursater, Goran Smedegard Abstract We have previously found by using the The effects of sulphasalazine on the pro- granulocyte as a model system that sulpha- duction of second messenger compounds in salazine inhibits cellular activation before activa- human granulocytes have been characterised tion of protein kinase C by interference with the by various stimuli. The increases in cytosolic synthesis of phosphoinositide derived second calcium, inositol trisphosphate, diacylgly- messenger compounds.6 As several cell types cerol, and phosphatidic acid (all important utilise phosphoinositide dependent signal trans- mediators of intracellular signal transduction) duction, sulphasalazine may modify a principal triggered by stimulation were inhibited by common mechanism for the regulation of sulphasalazine. The metabolites 5-amino- cell activity, which may explain the beneficial salicylic acid and sulphapyridine were less effects of the drug in a variety of diseases. potent inhibitors than the mother compound. Many of the stimuli used in the earlier studies It is concluded that sulphasalazine inhibits trigger an increase in cytosolic calcium as part of the synthesis of phosphoinositide derived the activation sequence. The increase in calcium second messenger compounds at the level of has, in a variety of cell systems, been found to phospholipase C or its regulatory guanosine depend on remodelling of phosphoinositides'3 5'-triphosphate (GTP) binding protein. In- (see fig 1). Ligation of a cell receptor leads to hibition of phosphatidic acid synthesis was the phospholipase C dependent hydrolysis of either due to the same mechanism, or to phosphatidylinositol-4,5-bisphosphate genera- interaction with a phospholipase D regulating ting two triggers of cell responses, namely GTP binding protein. diacylglycerol, an activator of protein kinase C,14 and inositol-1,4,5-trisphosphate, which (Ann Rheum Dis 1992; 51: 1230-1236) triggers the release of cell associated calcium.13 The link between the receptor and phospho- lipase C is in many cells a guanosine 5'- Sulphasalazine, a drug used for the treatment of trisphosphate (GTP) binding protein.'5 inflammatory bowel disease,' has during the last Several drugs have been shown to modulate http://ard.bmj.com/ decade also been shown to treat effectively other granulocyte responses such as superoxide pro- diseases of a presumably autoimmune nature, duction,16 and a few studies have indirectly such as rheumatoid arthritis, ankylosing associated the drug action with an interaction spondylitis,2 and psoriasis.3 with the synthesis of phosphoinositide derived The aetiology of tissue injury in rheumatoid second messenger molecules'7 18 and the GTP arthritis is unclear. A variety of cells, including binding protein.'9 granulocytes, have been suggested to contribute The purpose of this study was to evaluate on September 24, 2021 by guest. Protected copyright. to the initiation and propagation of the immune whether the inhibitory effects of sulphasalazine response in the rheumatoid synovium. Kitsis on cellular activation were related to the and Weissmann4 have reviewed the role of the production of second messenger compounds. neutrophil granulocyte as a key player in the We found that sulphasalazine inhibited the articular and extra-articular manifestations of production of inositol-1,4,5-trisphosphate and rheumatoid arthritis. They compared rheuma- consequently the increase in cytosolic calcium, toid joint inflammation to the Arthus reaction, a which indicated an interaction with either the neutrophil dependent interaction in which plasma membrane receptor, the associated GTP repeated exposure to an antigen results in the binding protein, or the phospholipase C. formation of immune complexes and activation Sulphasalazine still inhibited activation of cells of complement, causing an influx of granulo- stimulated with guanosine 5'-[y-thio]triphos- cytes and tissue destruction. phate (GTP[S]), a stimulus which bypasses the Sulphasalazine has been found to inhibit plasma membrane receptor. Department of Pharmacology, Kabi granulocyte activation, assessed as superoxide The production of phosphatidic acid, a meta- Pharmacia Therapeutics, production by cells activated with serum treated bolite of diacylglycerol, the other product of Uppsala, Sweden zymosan,5 chemotactic peptide N-formyl-L- phospholipase C activity, was also inhibited by G Carlin R Djursater methionyl-L-leucyl-L-phenylalanine (fMLP)6 7 sulphasalazine in cells unspecifically labelled in G Smedegard and immune complexes.8 Sulphasalazine the lipid glyceride backbone. Phosphatidic acid is formed of Correspondence to: has also been found to inhibit, for example, alternatively by hydrolysis phos- Dr Gunnar Carlin, granulocyte chemotaxis,9 lymphocyte prolifera- phatidylcholine; we found that sulphasalazine Kabi Pharmacia AB, S-751 82 Uppsala, Sweden. tion,'0 and interleukin 2 production" in also inhibited the production of radioactive Accepted for publication addition to monocyte production of interleukin phosphatidic acid in cells specifically labelled in 5 June 1992 1.12 phosphatidylcholine. Sulphasalazine inhibition ofhuman granulocyte activation 1231 37°C as described previously.2' Labelled granulocytes were washed and resuspended in Ann Rheum Dis: first published as 10.1136/ard.51.11.1230 on 1 November 1992. Downloaded from Hanks's balanced salt solution (HBSS, Gibco, p Paisley, UK) containing 10 mM LiCl. Each sample, containing 25 x 106 cells in 1 ml HBSS with LiCl, was preincubated with the test PLD i compound for 10 minutes at 37°C before chal- lenge with 0 1 ,IM fMLP (Calbiochem, La Jolla, PIP2 PC CA, USA). The reaction was terminated by addition of 7-5% trichloroacetic acid. Inositol- GDP .400' 1 ,4,5-trisphosphate was isolated by ion ex- IP3 DAG _ PA change chromatography as decribed pre- viously.21 Ca CYTOSOLIC CALCIUM The granulocytes, 1 x I08/ml, were incubated with 10 FtM FURA-2AM (Molecular Probes Inc., Eugene, OR, USA) as described by Korchak et al.22 The FURA-2 loaded cells were suspended to 25 x 106 cells/ml in ice cold PBS * 4 without Ca2' and Mg2e until used. The cells, 2-5 x I6/ml were preincubated in PBS either with or without Ca2+ and Mg2+ (in Protein Protein the latter case the buffer was supplemented with (inactive) (inactive) 1 mM EGTA) and test compound for two Protein-P minutes before the addition of stimulus. Fluo- (Active) rescence changes were monitored in a Shimadzu RF-5000 spectrophotometer equipped with a continuous magnetic stirring device at the dual excitation wavelengths of 340 and 380 nm, and emission at 510 nm. The concentration of Cell response cytosolic calcium was calculated by the ratio Figure I Schematic illustration ofthe partplayed by second messenger compounds in the method of Grynkiewicz et al.23 activation ofcells. The binding ofa ligand (L) to a membrane receptor (R) activates at 10 had considerable a phospholipase C (PLC) via the action ofa guanosine 5'-trisphosphate (GTP) Sulphasalazine ,umol/l bindingprotein (G). The activity ofthe GTP bindingprotein is regulated by absorbances at 340 and 380 nm. As the reduction its intrinsic GTPase activity, which hydrolyses GTP and thereby inactivates the of the emitted light was about 25% at the two protein. By hydrolysis ofphosphatidylinositol4,5-bisphosphate (PIP2), PLC generates wavelengths, however, sulphasalazine had only diacylglycerol (DAG), an activator ofprotein kinase C (PKC), and inositol-1,4,5- a negligible effect on the calculations of [Ca2+] trisphosphate (IP3), which triggers the release ofcell associated calcium and the subsequent http://ard.bmj.com/ activation ofa protein kinase (CaPK). Diacylglycerol isfurther phosphorylated to using the ratio method. phosphatidic acid (PA). Phosphatidic acid is alsoformed by a phospholipase D mediated (PLD) hydrolysis ofphosphatidylcholine (PC). Phosphatidic acid is subsequently dephosphorylated to DAG. GTP INDUCED SUPEROXIDE PRODUCTION The granulocytes were electropermeabilised Materials and methods essentially as described by Nasmith et al.24 Cells TEST COMPOUNDS were resuspended in permeabilisation buffer Sulphasalazine, sulphapyridine, and 5-amino- to 107 cells/ml and permeabilised with two on September 24, 2021 by guest. Protected copyright. salicylic acid were from Kabi Pharmacia discharges of 5 kV/cm from a 25 RF capacitor by (Uppsala, Sweden). using a Bio-Rad gene pulser apparatus equipped with a 0-8 ml cuvette. Permeabilised cells were used immediately (within a few minutes). The BUFFER permeabilisation buffer contained 10 mM Dulbecco's phosphate buffered saline (PBS) HEPES, 140 mM KC1, 1 mM EGTA, and 0-193 with, or when specifically stated without, mM CaC12 (giving a free [Ca2+] concentration of 0-9 mM Ca2" and 0-5 mM Mg2+ was from 100 nmol/l), 1 mM MgCl2, and 10 mM glucose Statens Veterinarmedicinska Anstalt (Uppsala, (pH 7-0, 295 mosM). Sweden). A 133 FtM solution of cytochrome c (type VI from horse heart, Sigma Chemical, St. Louis, MO, USA) in 750 1d permeabilisation buffer ISOLATION OF GRANULOCYTES containing the test compound was prewarmed Granulocytes were isolated from heparinised to 37°C. Thereafter 100 1t of a 20 mM NADPH blood from healthy volunteers, not using anti- solution was added immediately followed by 50 inflammatory
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