Interleukin 1, derived from human placenta, stimulates plasminogen activator activity in human articular chondrocytes. The stimulation of plasminogen activator activity can be abolished by preincubation of placental interleukin 1 with an antiserum to homogeneous 22K factor, a species of interleukin 1 beta, indicating that the stimulation of plasminogen activator activity is due to interleukin 1 and not contaminating factors. Chondrocytes produce three species of plasminogen activator, with apparent Mr approximately 50,000, 65,000 and 100,000 as determined after sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis with gels containing casein and plasminogen. Both placental interleukin 1 and 22K factor enhance the production of the species of Mr approximately 65,000 and 100,000. Comparison of the mobility of the plasminogen activator species on SDS-polyacrylamide gel electrophoresis with human urokinase (u-PA) and human melanoma tissue-type plasminogen activator (t-PA) and studies with antibodies to these enzymes indicate that the Mr approximately 50,000 species is a u-PA and the Mr approximately 65,000 a t-PA. The Mr approximately 100,000 species is possibly an enzyme-inhibitor complex. Interleukin 1 therefore appears to enhance the production of t-PA and a putative enzyme-inhibitor complex. Abolition of plasminogen activator activity in the fibrin plate assay with antibodies to t-PA and u-PA also confirms enhanced t-PA production on interleukin 1 stimulation, though there is also evidence for increased cell-associated production of u-PA.

The human interferon-beta-inducing 22K factor has been shown to have structural homologies with interleukin-1 beta (IL-1 beta) and some of the activities attributed to IL-1. We have shown that 22K factor, purified to homogeneity and endotoxin free, has connective tissue cell stimulating activities, indicating that these activities are due to a naturally occurring species of IL-1 beta and not contaminating factors. 22K factor stimulated the production of prostaglandin E, caseinase activity and plasminogen activator activity in human articular chondrocytes in culture. This cell system appears highly sensitive to 22K factor activity. 22K factor also stimulated the resorption of bovine nasal cartilage and neonatal mouse calvaria.

Interleukin-1 (IL-1) is the name given to a family of related proteins showing a variety of activities. It was originally shown to be produced by monocytes and macrophages but is now known to be produced by numerous cell types, including synovial cells. From the point of view of arthritis, its most interesting activities are those on connective tissue cells in vitro. These include stimulation of production of prostaglandins, plasminogen activator and metalloproteinases such as collagenase and proteoglycanase. IL-1 is also mitogenic for synoviocytes and bone cells, and can alter rates of production of extracellular matrix constituents. The presence of IL-1 in synovial fluids from rheumatoid and osteoarthritic joints and its actions on connective tissues in vitro suggest that IL-1 may play an important role in the pathogenesis of arthritis. There are several potential cellular sources of IL-1 in the inflamed rheumatoid joint and interactions between these cells, T lymphocytes and plasma cells may continually induce IL-1 so contributing to the chronicity of the disease. The mechanism of action of IL-1 on connective tissue cells is at present uncertain though preliminary studies suggest that IL-1 may induce cellular responses by stimulating phosphoinositide turnover and possibly protein kinase C activity.

Journal Article The Effects of Mononuclear Cell Factor/Interleukin-1 on the Plasminogen Activators Produced by Human Chondrocytes Get access R.A.D. Bunning, R.A.D. Bunning Search for other works by this author on: Oxford Academic PubMed Google Scholar P.R. Elford, P.R. Elford Search for other works by this author on: Oxford Academic PubMed Google Scholar J.E. Meats, J.E. Meats Search for other works by this author on: Oxford Academic PubMed Google Scholar H.J. Richardson, H.J. Richardson Search for other works by this author on: Oxford Academic PubMed Google Scholar R.G.G. Russell R.G.G. Russell Search for other works by this author on: Oxford Academic PubMed Google Scholar Rheumatology, Volume XXIV, Issue suppl_1, January 1985, Pages 118–121, https://doi.org/10.1093/rheumatology/XXIV.suppl_1.118 Published: 01 January 1985

We have investigated the relationship between the monokine interleukin 1 (IL-1) and the connective tissue-stimulating activities produced by monocytes such as mononuclear cell factor (MCF). Using almost exclusively human tissue we have monitored a wide range of MCF-like activities through the partial purification of IL-1 by gel filtration and isoelectric focusing. Activities measured include stimulation of chondrocytes to produce prostaglandins, plasminogen activator and proteoglycanase, enhancement of synovial cell proliferation, and stimulation of cartilage resorption, in addition to IL-1 (lymphocyte activating factor) activity. The activities described show the same molecular heterogeneity; the active material has similar potencies in the different systems, and removal of IL-1 activity by pretreatment with phenylglyoxal also results in loss of the connective tissue-stimulating activities. These results show that the factors responsible for this wide range of activities are very closely related to IL-1 and give further evidence in support of the possible involvement of IL-1 in the processes of joint destruction occurring in chronic inflammatory conditions such as rheumatoid arthritis.

In addition to their roles as potential regulators of tissue destruction, IL-l-hke factors can modulate the synthesis of matrix by skeletal and articular tissues. Considerable disparity exists, however, between the reports from different laboratories on the effects of these factors on the synthesis of matrix components MCF has variably been reported to stimulate or inhibit the synthesis of collagen by connective tissue cells. In this study we describe the inhibitory effects of monocyte-conditioned medium (MCM) on collagen biosynthesis by human chondrocytcs This inhibition does not appear to be dependent on increased production of prostaglandins since the effect persists in the presence of indomcthacin. Fractionation of MCM reveals that the inhibitory factor(s) copunfics with activities ascribed to MCF and IL-1 Partially purified IL-1 also inhibits the synthesis of matrix by human bone cells including that of the ostcoblast specific protein osteocalcin The inhibition of bone matrix synthesis is accompanied by a reduction in the activity of the ostcoblastic marker alkaline phosphatasc, possibly indicating that IL-1 inhibits the differentiation of bone forming cells

We have studied the biological activities of intercellular mediators derived from monocytcs (mononuclcarccll factor. MCF) and from synovium (synovial factor. SF). These factors may be related to catabolin, a protein that induces cartilage resorption in vitro In addition, there is now evidence to suggest that MCF may be related to the monokinc intcrleukin-1 (IL-1) In order to clarify the relationship between these factors we have partially purified MCF and SF and examined their biological activity using standard assays for IL-1. catabolin and MCF/SF We find that all connective tissue-stimulating activities copunfy with IL-1 and possess biochemical characteristics that arc indistinguishable from IL-1. The study indicates that both human monocytcs and synovium produce factors (originally termed MCF and SF) that are closely related to. or identical with, IL-1 and suggests that this protein may participate in cellular interactions that occur within the rheumatoid joint.