The physical interaction of particulates with resident mononuclear phagocytes is a consistent feature in certain forms of crystal-induced inflammation. In this study, we observed that monosodium urate crystals stimulated the rapid release of neutrophil chemotactic activity from monocytes, and that this activity steadily increased over 24 hours. Because the release of monocytederived neutrophil chemotactic activity was markedly diminished by pretreatment of the monocytes with cycloheximide, and was completely removed from conditioned media by adsorption to heparin-agarose, we addressed the possibility that monocyte-derived neutrophi1 chemotactic factor/interleukin-8 (IL-8), a heparinbinding neutrophil-activating polypeptide, might modulate these activities. Urate crystal-induced IL-8 secretion from monocytes was verified by radioimmuno- assay. In addition, an IL-%specific antibody markedly inhibited the neutrophil-activating capacity of the conditioned media from monocytes activated by urate crystals, as well as by inflammatory silica crystals. Last, IL-8 was significantly increased in gouty synovial fluids (range 3.0-16.8 ng/ml, mean 8.4 ng/ml, n = 6) relative to osteoarthritic synovial fluids (range 1.1-1.7 nglml, mean 1.5 ng/ml, n = 6) (P = 0.006). We conclude that microcrystal-induced secretion of IL-8 by mononuclear phagocytes may mediate a number of forms of crystalinduced inflammation.
T lymphocytes, macrophages, and oxidized lowdensity lipoprotein (Ox-LDL) are collocalized in early atherosclerotic lesions. Using a low-endotoxin in vitro system, we observed that Ox-LDL but not native LDL induced the production, by both freshly adherent human peripheral blood monocytes and human monocytic THP-1 cells, of the a chemokine interleukin (IL)-8, a potent chemoattractant for T lymphocytes. Marked IL-8 induction by Ox-LDL did not require IL-10 generation in THP-1 cells. Ox-LDL-induced chemokine production was selective, as Ox-LDL did not stimulate the production by THP-1 cells of the T-lymphocyte chemotactic f) chemokine macrophage inflammatory protein (MlP)-la. IL-8 induction increased in proportion to the extent of oxidation of LDL as measured by the content of lipid oxidation end products. To identify potentially active components of Ox-LDL, we tested malondialdehyde, an arachidonate-derived lipid oxidation product, and 9-hydroxyoctadecadienoic acid, an oxidation product of linoleate, the major polyunsaturated fatty acid in LDL, and observed that they Induced IL-8 generation in the absence of Ox-LDL. Furthermore, when most free lipid oxidation products were removed from Ox-LDL by dialysis, some IL-8-inducing activity was released into the dialysate. However, the major IL-8-inducing activity was not dialyzable. To address the nature of the LDL particle modification required to induce IL-8, acetylated or malondialdehyde-trcated native LDL particles were monitored for activity. Neither procedure rendered LDL capable of inducing IL-8. However, phospholipase A^-treated LDL induced THP-1 cell expression of IL-8. Thus, Ox-LDL induced a chemokine in monocytic THP-1 cells by a mechanism that did not absolutely require IL-1/3, appeared to be predominantly mediated by particle-associated and nondiffusible end products of lipid degradation, and could be reproduced by phospholipase A 2 treatment of LDL. The Ox-LDL-induced generation from monocyte/macrophages of selected chemokines that chemoattract T lymphocytes may contribute to atherogenic and inflammation-regulating properties of Ox-LDL {ArterioscUr Thromb. 1994;14:47-53.) Key Words • oxidized LDL • chemokines • interleukin-8 • macrophage inflammatory protein-la • interleukin-1 • T lymphocytes • atherosclerosis T he cellular components of certain atherosclerotic lesions include T lymphocytes, which are not usually present within the normal arterial wall.14 Within early atherosclerotic lesions (ie, intimal thickening and fatty streaks), T cells and macrophages are collocalized in significant numbers.5 T lymphocytes also comprise up to 20% of the cells in the fibrous cap.
Tissue deposits of basic calcium phosphate (BCP) crystals are associated with various clinical manifestations of inflammation. We addressed the possibility that native proteins modify the ability of hydroxyapatite (HA) crystals to stimulate human inflammatory cells. Neutrophil superoxide release and chemiluminescence in response to HA crystals (0.3-4.0 mg/ml) were blunted by serum and plasma. Inhibitory activity was progressively removed from serum by sequential adsorption with HA crystals, suggesting that the inhibitors were crystal-bound proteins. Thus, we characterized HA crystal-bound plasma proteins by O'Farrell gels: Fibronectin, transferrin, albumin, a,-HS glycoprotein (AHSG), al-proteinase inhibitor, a,-acid glycoprotein, Gc globulin, haptoglobin, and high density lipoprotein apolipoproteins were major bound species. Of these, AHSG was the most active inhibitor of HA-induced neutrophil superoxide release, and this glycoprotein partially (60%) restored inhibitory activity to HAadsorbed serum. AHSG also bound in vitro to the related BCP crystal, octacalcium phosphate, but only minimally to calcium pyrophosphate dihydrate crystals and monosodium urate crystals. Suppressive effects on neutrophil stimulation exhibited by AHSG were also specific for BCP crystals. AHSG was present in noninflammatory synovial fluids bound to synthetic HA crystals in vitro, and AHSG could be detected on native synovial fluid HA crystals. We conclude that the binding of AHSG may modulate the inflammatory potential of BCP crystals.Synthetic hydroxyapatite (HA) crystals directly stimulate human neutrophils in vitro (1) and consistently provoke self-limited acute inflammation when injected into the articular and pleural cavities of animals, into the foot pad of rats, and into the dermis of human volunteers (2-4). Furthermore, acute periarticular inflammation, and less commonly, an acute synovitis that is similar to acute gout in presentation and in response to therapy, are associated with the presence of HA crystals and related basic calcium phosphates (BCP) (2,3,5-8).
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