Cytokine-induced Chemoattractant Research Articles

Kinetics of α2-macroglobulin and α1-acid glycoprotein in rats subjected to repeated acute inflammatory stimulation

The kinetics of alpha(2)-macroglobulin (alpha2M) and alpha(1)-acid glycoprotein (AAG) in rats repeatedly stimulated with intramuscular injections of turpentine oil at doses 0.05 and 0.4 mL/rat were investigated. Mean serum levels of alpha2M peaked at 48 h after the first turpentine oil injection, reaching 1.74 and 2.36 mg/mL at 0.05 and 0.4 mL/rat, respectively. AAG peaks were also observed at 48 h after injection, and the mean values were 2.02 and 2.53 mg/mL, respectively. These peak values of alpha2M and AAG differed significantly between the 0.05 and 0.4 mL/rat injection groups. Mean serum levels of interleukin-6 (IL-6) at 0.05 mL/rat were 52.61 pg/mL at 12 h, 48.86 pg/mL at 36 h and 81.93 pg/mL at 84 h after the first injection. Mean IL-6 serum levels at 0.4 mL/rat were 215.24 pg/mL at 12 h, 56.33 pg/mL at 36 h and 39.25 pg/mL at 84 h after the first injection. Mean serum levels of cytokine-induced chemoattractant-1 (CINC-1) at a dose of 0.05 mL/rat were 5.70 ng/mL at 12 h, 5.58 ng/mL at 36 h and 4.58 ng/mL at 84 h after the first injection. Mean serum levels of CINC-1 after injection at 0.4 mL/rat were 11.57 ng/mL at 12 h, 4.68 ng/mL at 36 h and 4.42 ng/mL at 84 h. Serum levels of IL-6 differed significantly at 12, 24, 72 and 84 h, while those of CINC-1 differed significantly at 12, 24, 48 and 96 h between the 0.05 and 0.4 mL/rat injection groups. Differences in peak serum levels in the 0.05 and 0.4 mL/rat groups were attributed to differences in the production of IL-6 and CINC-1, which are thought to contribute to alpha2M and AAG production.

GENE EXPRESSION PROFILING IN SPLEENS OF DEOXYNIVALENOL-EXPOSED MICE: IMMEDIATE EARLY GENES AS PRIMARY TARGETS

Exposure to the trichothecene mycotoxin deoxynivalenol (DON) alters immune functions in vitro and in vivo. To gain further insight into DON's immunotoxic effects, microarrays were used to determine how acute exposure to this mycotoxin modulates gene expression profiles in murine spleen. B6C3F1 mice were treated orally with 25mg/kg body weight DON, and 2h later spleens were collected for macroarray analysis. Following normalization using a local linear regression model, expression of 116 out of 1176 genes was significantly altered compared to average expression levels in all treatment groups. When genes were arranged into an ontology tree to facilitate comparison of expression profiles between treatment groups, DON was found primarily to modulate genes associated with immunity, inflammation, and chemotaxis. Real-time polymerase chain reaction was used to confirm modulation for selected genes. DON was found to induce the cytokines interleukin (IL)-1α, IL-1β, IL-6 and IL-11. In analogous fashion, DON upregulated expression of the chemokines macrophage inhibitory protein-2 (MIP-2), cytokine-induced chemoattractant protein-1 (CINC-1), monocyte chemoattractant protein (MCP)-1, MCP-3, and cytokine-responsive gene-2 (CRG-2). c-Fos, Fra-, c-Jun, and JunB, components of the activator protein-1 (AP-1) transcription factor complex, were induced by DON as well as another transcription factor, NR4A1. Four hydrolases were found to be upregulated by DON, including mitogen-activated protein kinase phosphatase 1 (MKP1), catalytic subunit β isoform (CnAβ), protein tyrosine phosphatase receptor type J (Ptprj), and protein tyrosine phosphatase nonreceptor type 8 (Ptpn8), whereas three other hydrolases, microsomal epoxide hydrolase (Eph) 1, histidine triad nucleotide binding protein (Hint), and proteosome subunit β type 8 (Psmb8) were significantly decreased by the toxin. Finally, cysteine-rich protein 61 (CRP61) and heat-shock protein 40 (Hsp40), genes associated with signaling, were increased, while Jun kinase 2 (JNK2) was decreased. Taken together, data suggest that DON upregulated the expression of multiple immediate early genes, many of which are likely to contribute to the complex immunological effects reported for this and other trichothecenes.

Effect of a Novel Non-steroidal Anti-inflammatory Drug (M-5011) on Cytokine Levels in Rats With Monosodium Urate Crystal-Induced Pleurisy

We evaluated the effects of a new non-steroidal anti-inflammatory drug (NSAID), d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (M-5011), and indomethacin on the production of arachidonate metabolites and pro-inflammatory cytokines in male Sprague-Dawly rats with monosodium urate crystal (MSU)-induced pleurisy. Levels of tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6 in the pleural exudate were determined by biological assays, while prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and cytokine-induced chemoattractant-1 (CINC-1) levels were quantified by enzyme immunoassays. Orally administered M-5011 (5 mg/kg) decreased the pleural exudate volume at 3 and 4 hr after MSU injection. Indomethacin (10 mg/kg) decreased the volume at 3–5 hr. These drugs reduced the number of leukocytes in the pleural cavity at 6 hr. Both NSAIDs also reduced the content of PGE2 in the exudate without affecting LTB4 levels. Increased productions of both IL-6 and CINC-1 in the exudate were reduced by pretreatment with M-5011 or indomethacin, and TNF levels in the exudate were increased by pretreatment of these drugs. Thus, M-5011 inhibits the production of both IL-6 and CINC-1 at lower doses than those of indomethacin, and the inhibitory effect of M-5011 on CINC-1, but not IL-6, may partly contribute to the inhibition of leukocyte infiltration in rats with MSU-induced pleurisy.

Phagocytes and acute lung injury: dual roles for interleukin-1.

Interleukin-1 (IL-1) and neutrophils are increased in lungs of patients with the acute respiratory distress syndrome (ARDS). We found that rats given IL-1 intratracheally rapidly developed lung neutrophil accumulation and a neutrophil-dependent acute edematous lung leak. Lung leak was associated with increased lung lavage cytokine-induced chemoattractant (CINC) levels and increased oxidative stress that was manifested by increased exhaled H2O2 levels and increased lung oxidized glutathione levels. IL-1-induced lung leak was decreased by treatment with superoxide dismutase (SOD), dimethylsulfoxide (DMSO), supercritical fluid-aerosolized vitamin E, interleukin-1-receptor antagonist (IL-1ra), or liposome-associated PGE1 (Lip-PGE1). Importantly, Lip-PGE1 treatment also reduced ventilator dependence in a small clinical study of ARDS patients. Another series of investigations revealed that IL-1 pretreatment could prevent lung leak in rats given IL-1 intratracheally. These findings point to the possible dual effects of IL-1 with respect to the development of acute lung injury.