Functional discrimination between interleukin 6 and interleukin 1

Helle, M.; and, Leonie Boeije And; Aarden, Lucien A.

doi:10.1002/eji.1830181010

Cited by 408 publications

(175 citation statements)

References 35 publications

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“…In the absence of antibodies to canine IL-6, the possibility that other factors contribute to the proliferation of B9 cells cannot be ruled out; however, the activity is most likely to be due to IL-6. On testing a number of human and murine cytokines, alone and in combination (IL-la, IL-I@, IL-2, IL-3, IL-4, TNFa, IFNy, and GM-CSF), Helle et a1 (11) found that only murine IL-4 showed any activity toward B9 cells, and that IL-4 was only 0.02% as active as IL-6. There are many possible sources of the IL-6 present in synovial fluid.…”

Section: Discussionmentioning

confidence: 99%

“…IL-6 was measured by the B9 assay (11). Briefly, B9 murine hybridoma cells (5,00O/well) were cultured in 96-well flat-bottom microtiter plates in RPMI 1640 containing 5% fetal calf serum (FCS), 100 units/ml penicillin, and 100 pg/ml streptomycin.…”

Section: Methodsmentioning

confidence: 99%

“…B9 cells respond to IL-6 derived from several species including canine IL-6 (12,13), but are not stimulated by IL-la, IL-lp, IL-2, IL-3, IL-4, TNFa, interferon-y (IFNy), or granulocyte-macrophage colony-stimulating factor (GM-CSF) (11). Results are the mean of 2 replicates and are expressed as picograms per milliliter of human 11-6 equivalents; the limit of detection in our assay was 10 pg/ml.…”

Section: Methodsmentioning

confidence: 99%

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Elevated synovial fluid levels of interleukin‐6 and tumor necrosis factor associated with early experimental canine osteoarthritis

Venn

Nietfeld

Duits

et al. 1993

Arthritis & Rheumatism

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Objective. To measure levels of cytokines, proteases, and glycosaminoglycans (GAG) in synovial fluid (SF) From the knees of animals with experimental osteoarthritis (OA) and from their contralateral (control) knees, and to compare and correlate these values with each other as well as with measures of proteoglycan synthesis in the corresponding articular cartilage. This study will help to identify cytokines of potential importance in the early stages of the development of OA.Methods. OA was induced in 12 mature animals by sectioning the anterior cruciate ligament. After 3 months, SF From the operated and contralateral (control) knee joints was assayed for interleukind (IL-6), tumor necrosis Factor (TNF), IL-1, latent metalloproteinase, and sulfated GAG. Proteoglycan synthesis in the corresponding articular cartilage was also measured.Results. IL-6 levels in SF from the operated joint compared with the control joint were significantly ele- Submitted for publication July 9, 1992; accepted in revised form January 6, 1993. vated in 11 of 12 animals. TNF levels were also elevated in 10 of 11 SF samples from operated joints, but to a lesser extent than those of IL-6. IL-1 and IL-1 inhibitors were undetectable in either the operated or control joint SF. The GAG concentration was elevated in SF from experimental OA joints. This elevation correlated with that of TNF, but not IL-6. There was no significant difference in the concentration of APMA-activatable metalloproteinase. The rate of proteoglycan synthesis was higher in the cartilage from the operated joint in 8 of 12 animals, and the mean rate of synthesis was significantly higher than in the control joint. There was a positive correlation between this increase in cartilage proteoglycan synthesis (operated versus control) and the increase in SF IL-6, but there was no correlation with the levels of TNF or GAG.Conclusion. This is the first study of SF levels of cytokines in early experimental OA. Our results show surprisingly high levels of IL-6 in operated joints, where the cytokine could act directly on the chondrocytes, and thus play a role in mediating their responses to cartilage injury.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Elevated synovial fluid levels of interleukin‐6 and tumor necrosis factor associated with early experimental canine osteoarthritis

Venn

Nietfeld

Duits

et al. 1993

Arthritis & Rheumatism

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“…B9 cells are insensitive to IL-la, IL-lP, IL-2, IL-3, IL-4, tumor necrosis factor a, interferon-y, and granulocytemacrophage colony-stimulating factor (17). In previous control experiments, the IL-6 activity in the cartilage culture media was assessed by the addition (in the B9 assay) of antibodies raised against highly purified rHuIL-6 (8).…”

Section: Methodsmentioning

confidence: 99%

Antisense oligonucleotides, a novel tool for the control of cytokine effects on human cartilage. focus on interleukins 1 and 6 and proteoglycan synthesis

Nietfeld¹,

Duits²,

Tilanus³

et al. 1994

Arthritis & Rheumatism

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Objective. To prevent the negative effects of interleukin-1 (IL-1) and IL-1-induced IL-6 on cartilage proteoglycan (PG) synthesis, we used an antisense oligonucleotide (ASO) specific for IL-6 messenger RNA (mRNA) to inhibit IL-6 production.Methods. Explants of human articular cartilage were cultured in the presence or absence of IL-6-ASO, IL-1, and exogenous IL-6. As metabolic parameters, cartilage production of IL-6 was determined in the B9 bioassay and PG as incorporation of "SO4.Results. The IL-&AS0 prevented IL-1-induced production of IL-6 in the cartilage explants, as well as IL-1-induced inhibition of PG synthesis. This inhibition was restored, despite the presence of IL-&ASO, when exogenous IL-6 was added. A control AS0 (not specific for IL-6 mRNA) was not effective.Conclusion. The IL-&AS0 used can penetrate the extracellular matrix of articular cartilage, enter the chondrocytes, and inhibit the IL-1-induced production of IL-6. Furthermore, IL-&AS0 can prevent the IL-1-induced inhibition of cartilage PG synthesis. The effect of exogenous IL-6 shows that IL-1 requires IL-6 for inhibition of PG synthesis.When explants of human articular cartilage are cultured in the presence of interleukin-1 (IL-l), the synthesis of proteoglycans (PG), essential structural components of the extracellular matrix of articular cartilage (1-5), is inhibited. This inhibition of chondrocyte PG synthesis is believed to play a key role in the destruction of cartilage during rheumatoid arthritis. Furthermore, IL-l induces the chondrocytes to produce IL-6 in a dose-dependent way, as has been shown (6,7).Our previous results (8) strongly suggested that for chondrocytes, IL-6 is not the effector of the IL-I-induced inhibition of PG synthesis. We found that (a) exogenous IL-6 on its own was more than 1,000 times less potent than IL-1 as an inhibitor of chondrocyte PG synthesis; and (b) at an IL-1 concentration that caused complete inhibition of PG synthesis, IL-6 production could still be increased more than 2-fold by increasing the concentration of IL-1.Nevertheless, IL-6 plays a crucial role in IL-1-induced inhibition of PG synthesis. Our previously reported experiments with antibodies against IL-6 showed that the presence of the IL-1-induced IL-6 is required for IL-1 to be able to inhibit the synthesis of PG in the chondrocytes (8). In an experimental arthritis model, application of such antibodies to bind IL-6 will eventually cause immunologic problems because of the immunogenicity of the antibodies. We have therefore sought other ways to block the IL-1-induced IL-6 production in cartilage.Recent in vivo studies (9,lO) have described the presence of so-called "antisense" nucleotides that inhibit (or regulate) the translation of messenger RNA (mRNA) by the formation of a duplex. In the present study, we used antisense oligonucleotides (ASO) that are specific for IL-6 mRNA. We investigated the effect on IL-1-induced production of IL-6 in human articular cartilage explants and the effect on IL-1-induced inhibition of PG synthesis.

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“…Immediately after death blood was taken by cardiac puncture. The IL 6 concen trations in the sera obtained were measured using the B-9 cell line [5], and IL1 concentrations were measured using D10.G4.1 cells [13], the D10(N4)M subclone; both assays have been described in detail [14]. Similarly, serum concentra tions of IL 6 and IL 1 were measured after an i.p.…”

Section: Pharmacokinetics Of Ril 6 and Ril 1 And Induction Of Ilmentioning

confidence: 99%

Comparison of the effects of recombinant interleukin 6 and recombinant interleukin 1 on nonspecific resistance to infection

1989

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Interleukin 1 (IL 1) is a potent enhancer of nonspecific resistance to infection in mice. Since IL1 also induces interleukin 6 (IL6), we tested the hypothesis that IL 6 medi ates the effect of IL1 on nonspecific resistance. In a lethal Pseudomonas aeruginosa infection in granulocytopenic mice, in which 80 ng of recombinant human IL la pro tects against death, IL 6 appeared to be much less effective. Dosages of 8 ng, 80 ng and 320 ng IL 6 did not differ from the control, whereas 800 ng had a marginal protective effect (0.05 < p < 0.1). IL1 and IL 6 did not potentiate each other in ani mals treated with suboptimal dosages of both cytokines. Numbers of bacteria cultured from the blood, thigh muscle, liver, spleen, and kidney were similar in animals treated with 800 ng IL 6 and in control animals, arguing against activation of microbicidal mechanisms. The serum concentration profile of IL 6 after an i.p. injection of 80 ng IL1 was similar to that after 80 ng IL 6 i.p. Only minute amounts of IL1 were detected in serum after an i.p. injection of IL 6. Taken these data together, it appears that increased resistance to infection induced by IL1 is not mediated by IL 6.

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Functional discrimination between interleukin 6 and interleukin 1

Cited by 408 publications

References 35 publications

Elevated synovial fluid levels of interleukin‐6 and tumor necrosis factor associated with early experimental canine osteoarthritis

Elevated synovial fluid levels of interleukin‐6 and tumor necrosis factor associated with early experimental canine osteoarthritis

Antisense oligonucleotides, a novel tool for the control of cytokine effects on human cartilage. focus on interleukins 1 and 6 and proteoglycan synthesis

Comparison of the effects of recombinant interleukin 6 and recombinant interleukin 1 on nonspecific resistance to infection

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