GENERATION OF INFLAMMATORY CYTOKINES IN ZYMOSAN-INDUCED PLEURISY IN RATS: TNF INDUCES IL-6 AND CYTOKINE-INDUCED NEUTROPHIL CHEMOATTRACTANT (CINC) IN VIVO

doi:10.1006/cyto.1998.0376

Cytokine

Volume 10, Issue 12, December 1998, Pages 956-963

https://doi.org/10.1006/cyto.1998.0376 Get rights and content

Abstract

Levels of inflammatory cytokines tumour necrosis factor (TNF), interleukin 1 (IL-1), IL-6, and cytokine-induced neutrophil chemoattractant (CINC), which is a member of the α-chemokine family in rats, were measured in the pleural exudates during zymosan-induced pleurisy to examine the relationship between the local production of cytokines and the inflammatory reaction. All four cytokine levels in the pleural exudate began to increase after 1–2 h, preceding the influx of neutrophils, and peaked after 4–5 h. Thereafter, these cytokine levels declined after 24 h, whereas the exudate volume still continued to increase and leukocyte number reached a plateau. Concomitant injection of actinomycin D (10 μg) with zymosan markedly suppressed the neutrophil infiltration, parallel with CINC production in the pleural exudate at 4 h. A transient elevation of IL-6 level, peaking at 5 h, and subsequent rise in the level of an acute-phase protein, T-kininogen, were also observed in the plasma. When recombinant human TNF-α (rhTNF-α) (20 000 U) was intrapleurally injected a rapid increase in pleural CINC level, followed by neutrophil infiltration, and a sharp rise in IL-6 level in the plasma, followed by an increase in T-kininogen, were demonstrated. These results suggest that CINC produced in the pleural exudate may participate in neutrophil infiltration, that IL-6 induced in the plasma stimulates T-kininogen production, and that endogenous TNF may be partly involved in the induction of CINC and IL-6 in this zymosan inflammation.

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Edema is one of the obvious indicators of inflammation and a crucial factor to take into account when assessing a substance's capacity to reduce inflammation. We aimed to evaluate the antiedematogenic and anti-inflammatory profile of the hydroethanolic barks extract of Ximenia americana (HEXA). The possible antiedematogenic and anti-inflammatory effect of EHXA (50, 100 mg/kg and 250 mg/kg v.o) was evaluated using the paw edema induced by carrageenan, zymosan, dextran, CFA and by different agents inflammatory (serotonin, histamine, arachidonic acid and PGE₂), and pleurisy model induced by carrageenan and its action on IL-1β and TNF-α levels was also evaluated. HEXA demonstrated a significant antiedematogenic effect at concentrations of 50, 100 and 250 mg/kg on paw edema induced by carrageenan, zymosan and dextran. However, the concentration of 50 mg/kg as standard, demonstrating the effect in the subchronic model, induced CFA with inhibition of 59.06 %. In models of histamine-induced paw edema, HEXA showed inhibition of − 30 min: 40.49 %, 60 min: 44.70 % and 90 min: 48.98 %; serotonin inhibition - 30 min: 57.09 %, 60 min: 66.04 % and 90 min: 61.79 %; arachidonic acid inhibition - 15 min: 36.54 %, 30 min: 51.10 %, 45 min: 50.32 % and 60 min: 76.17 %; and PGE₂ inhibition - 15 min: 67.78 %, 30 min: 62.30 %, 45 min: 54.25 % and 60 min: 47.92 %. HEXA significantly reduced (p < 0.01) leukocyte migration in the pleurisy model and reduced TNF-α and IL-1β levels in pleural lavage (p < 0.0001). The results showed that HEXA has the potential to have an antiedematogenic impact in both acute and chronic inflammation processes, with a putative mode of action including the suppression or regulation of inflammatory mediators.
Mechanistic evaluation of a novel cyclohexenone derivative's functionality against nociception and inflammation: An in-vitro, in-vivo and in-silico approach
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It has been reported that GABAergic agonists may augment the anti-nociceptive effect of a centrally acting analgesic such as morphine (Sawynok, 1984), hence, it is conceivable that GABA receptor agonist administration may represent a therapeutic option for the management of both chronic and acute pain (McCarson and Enna, 2014) or as a combination of GABA with opioid receptor related therapies. The acetic acid induced abdominal constriction assay is a tonic visceral pain model frequently utilized for monitoring the anti-nociceptive action of drugs (Utsunomiya et al., 1998). Although it is a very sensitive test, it cannot distinguish whether the nociceptive activity is peripherally or centrally mediated (Chen et al., 1995).
The synthesis of a novel cyclohexanone derivative (CHD; Ethyl 6-(4-metohxyphenyl)-2-oxo-4-phenylcyclohexe-3-enecarboxylate) was described and the subsequent aim was to perform an in vitro, in vivo and in silico pharmacological evaluation as a putative anti-nociceptive and anti-inflammatory agent in mice. Initial in vitro studies revealed that CHD inhibited both cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzymes and it also reduced mRNA expression of COX-2 and the pro-inflammatory cytokines TNF-α and IL-1β. It was then shown that CHD dose dependently inhibited chemically induced tonic nociception in the abdominal constriction assay and also phasic thermal nociception (i.e. anti-nociception) in the hot plate and tail immersion tests in comparison with aspirin and tramadol respectively. The thermal test outcomes indicated a possible moderate centrally mediated anti-nociception which, in the case of the hot plate test, was pentylenetetrazole (PTZ) and naloxone reversible, implicating GABAergic and opioidergic mechanisms. CHD was also effective against both the neurogenic and inflammatory mediator phases induced in the formalin test and it also disclosed anti-inflammatory activity against the phlogistic agents, carrageenan, serotonin, histamine and xylene compared with standard drugs in edema volume tests. In silico studies indicated that CHD possessed preferential affinity for GABA_A, opioid and COX-2 target sites and this was supported by molecular dynamic simulations where computation of free energy of binding also favored the formation of stable complexes with these sites. These findings suggest that CHD has prospective anti-nociceptive and anti-inflammatory properties, probably mediated through GABAergic and opioidergic interactions supplemented by COX-2 and 5-LOX enzyme inhibition in addition to reducing pro-inflammatory cytokine expression. CHD may therefore possess potentially beneficial therapeutic effectiveness in the management of inflammation and pain.
Enhanced anti-inflammatory benefits of meloxicam-loaded lipid-core nanocapsules in a mouse pleurisy model: A comparative study with a free form drug
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The development of new treatments for inflammation continues to be of high interest, since long-acting effect is critical for patients. We investigated whether meloxicam-loaded lipid-core nanocapsules (M-NC) have an anti-inflammatory action superior to a free drug (M-F) on a mouse pleurisy model, by analyzing the time-course of leukocytes migration in the pleural fluid. Male adult Swiss mice were divided into six groups for each time (24; 48 and 72 h) and were pretreated with blank nanocapsules (17 ml/kg) or M-NC (5 mg/kg) or free meloxicam (M-F) (5 mg/kg). After pretreatments, mice received saline (0.9%) or carrageenan (Cg) (1%) into pleural cavity. Four hours after Cg or saline administration, animals were killed, pleural cavity was washed and pleural fluid was collected for the determination of total leukocytes. Cytokines levels, differential leukocyte count and α-1-acid glycoprotein (AGP) levels were determined only at 48 h of pretreatment, which had effect on total leukocyte count. M-NC were effective against the increase in total and differential leukocyte counts and pleural exudate caused by Cg, while M-F had no effect. M-NC had superior effect to M-F against the increase in cytokines and AGP levels induced by Cg. In summary, M-NC had a superior anti-inflammatory effect to free drug in Cg-induced pleurisy, supporting the idea that the inflammatory process in tissues facilitates the vectorization of polymeric nanoparticles.
Anti-inflammatory effect of Schinus terebinthifolius Raddi hydroalcoholic extract on neutrophil migration in zymosan-induced arthritis
2015, Journal of Ethnopharmacology
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NF-κB is a pivotal regulator in the expression of many pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, and chemokines, e.g., CXCL-1/KC (Underhill, 2003), detected at early time points in murine models of inflammation (Ajuebor et al., 1999). Previous reports have shown that TNF-α, IL-1, IL-6, and CINC (a member of the α-CXC chemokine family in rats) were sequentially produced during the early stages of zymosan-induced pleurisy in rats (Utsunomiya et al., 1998). Our results observed the production of IL-6 and CXCL-1/KC 4 h after zymosan intra-thoracic injection in mice.
Schinus terebinthifolius is a species of plant from the Anacardiaceae family, which can be found in different regions of Brazil. Schinus is popularly known as aroeirinha, aroeira-vermelha, or Brazilian pepper. In folk medicine, S. terebinthifolius is used for several disorders, including inflammatory conditions, skin wounds, mucosal membrane ulcers, respiratory problems, gout, tumors, diarrhea and arthritis. According to chemical analyses, gallic acid, methyl gallate and pentagalloylglucose are the main components of hydroalcoholic extracts from S. terebinthifolius leaves. In the present study, we demonstrated the ability of a hydroalcoholic extract to inhibit cell migration in arthritis and investigated the mechanisms underlying this phenomenon.
The anti-inflammatory effect of S. terebinthifolius hydroalcoholic leaf extract (ST-70) was investigated in a zymosan-induced experimental model of inflammation. Male Swiss and C57Bl/6 mice received zymosan (100 µg/cavity) via intra-thoracic (i.t.) or intra-articular (i.a.) injection after oral pre-treatment with ST-70. The direct action of ST-70 on neutrophils was evaluated via chemotaxis.
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Our results demonstrated significant anti-inflammatory effects of ST-70, suggesting a putative use of this herb for the development of phytomedicines to treat inflammatory diseases, such as joint inflammation.
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The results showed that osthole could attenuate lung inflammation by inhibiting the influx of PMNs into the lung tissue. Activating cytokines is the key process of inflammatory reaction [17]. These cytokines can induce chemotaxis to attract migrating granulocytes, on the other hand, leukocytes could produce further cytokines and proinflammatory mediators [18].
Osthole has been reported to possess a variety of pharmacological activities, such as antiinflammatory effect. In the present study, we have investigated the effect of osthole on lung inflammation associated with carrageenan-induced pleurisy in rats. The result showed that osthole could inhibit significantly pleural exudates formation and PMNs infiltration. Histological examination revealed osthole could reduce lung inflammation in rats treated with carrageenan. The myeloperoxidase (MPO) level was examined in pleural exudates. The result showed that osthole could attenuate MPO level in pleural exudates. Further studies showed osthole could decrease tumor necrosis factor alpha (TNF-α) and interleukin 1beta (IL-1β) levels in the lungs. Taken together, the present results suggested that osthole could inhibit lung inflammation on carrageenan-induced pleurisy in rats and that could be related to a reduction of PMNs infiltration and release of inflammatory factors.
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Pro-inflammatory cytokines TNF-α and IL-1β are released in the pleural exudates induced by carrageenan in rats (Utsunomiya et al., 1991). These cytokines can cause chemotaxis to attract granulocytes and monocytes, migrating leukocytes produce, in turn, further cytokines, such as TNF-α and IL-1β, and other pro-inflammatory mediators (Utsunomiya et al., 1998). These cytokines have been proposed as crucial mediators for the development of carrageenan-induced pleurisy and for the accumulation of leukocytes in the inflammatory site.
Accumulative evidences have showed that some coumarin derivatives have significantly anti-inflammatory effects. To investigate the potential anti-inflammatory effect of compound IMMLG5521, a novel coumarin derivative, carrageenan-induced pleurisy model in rats was employed. The results showed that IMMLG5521 (5, 10 and 20 mg/kg) exhibited anti-inflammatory effects, reducing pleural exudate formation, decreasing total number of inflammation cells and polymorphonuclear leukocytes infiltration, attenuating histological injury and reducing TNF-α, IL-1β, MIP-2 and IL-8 release. Further investigation revealed that the compound may exert its anti-inflammatory effect via inhibiting nuclear translocation of NF-кB in inflammatory cells collected from pleural exudates. Taken together, the present results suggested that IMMLG5521 inhibited acute inflammation in carrageenan-induced pleurisy model that could be, in part, related to a reduction of release of inflammatory factors, another part may be related to an inhibition of NF-кB activation.

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^f1: Correspondence to Sachiko Oh-ishi, Department of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108, Japan

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Regular articleGENERATION OF INFLAMMATORY CYTOKINES IN ZYMOSAN-INDUCED PLEURISY IN RATS: TNF INDUCES IL-6 AND CYTOKINE-INDUCED NEUTROPHIL CHEMOATTRACTANT (CINC) IN VIVO

Abstract

Regular article
GENERATION OF INFLAMMATORY CYTOKINES IN ZYMOSAN-INDUCED PLEURISY IN RATS: TNF INDUCES IL-6 AND CYTOKINE-INDUCED NEUTROPHIL CHEMOATTRACTANT (CINC) IN VIVO