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Tilapia hepcidin 2-3 peptide modulates lipopolysaccharide-induced cytokines and inhibits tumor necrosis factor-alpha through cyclooxygenase-2 and phosphodiesterase 4D.

ABSTRACT: The antimicrobial peptide, tilapia hepcidin (TH) 2-3, belongs to the hepcidin family, and its antibacterial function has been reported. Here, we examined the TH2-3-mediated regulation of proinflammatory cytokines in bacterial endotoxin lipopolysaccharide (LPS)-stimulated mouse macrophages. The presence of TH2-3 in LPS-stimulated cells reduced the amount of tumor necrosis factor (TNF)-? secretion. From a microarray, real-time polymerase chain reaction (PCR), and cytokine array studies, we showed down-regulation of the proinflammatory cytokines TNF-?, interleukin (IL)-1?, IL-1?, IL-6, and the prostaglandin synthesis gene, cyclooxygenase (COX)-2, by TH2-3. Studies with the COX-2-specific inhibitor, melaxicam, and with COX-2-overexpressing cells demonstrated the positive regulation of TNF-? and negative regulation of cAMP degradation-specific phosphodiesterase (PDE) 4D by COX-2. In LPS-stimulated cells, TH2-3 acts like melaxicam and down-regulates COX-2 and up-regulates PDE4D. The reduction in intracellular cAMP by TH2-3 or melaxicam in LPS-stimulated cells supports the negative regulation of PDE4D by COX-2 and TH2-3. This demonstrates that the inhibition of COX-2 is among the mechanisms through which TH2-3 controls TNF-? release. At 1 h after treatment, the presence of TH2-3 in LPS-stimulated cells had suppressed the induction of pERK1/2 and prevented the LPS-stimulated nuclear accumulation of NF-?B family proteins of p65, NF-?B2, and c-Rel. In conclusion, TH2-3 inhibits TNF-? and other proinflammatory cytokines through COX-2-, PDE4D-, and pERK1/2-dependent mechanisms.

SUBMITTER: Rajanbabu V

PROVIDER: S-EPMC2945552 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Tilapia hepcidin 2-3 peptide modulates lipopolysaccharide-induced cytokines and inhibits tumor necrosis factor-alpha through cyclooxygenase-2 and phosphodiesterase 4D.

Rajanbabu Venugopal V Pan Chieh-Yu CY Lee Shang-Chun SC Lin Wei-Ju WJ Lin Ching-Chun CC Li Chung-Leung CL Chen Jyh-Yih JY

The Journal of biological chemistry 20100730 40

The antimicrobial peptide, tilapia hepcidin (TH) 2-3, belongs to the hepcidin family, and its antibacterial function has been reported. Here, we examined the TH2-3-mediated regulation of proinflammatory cytokines in bacterial endotoxin lipopolysaccharide (LPS)-stimulated mouse macrophages. The presence of TH2-3 in LPS-stimulated cells reduced the amount of tumor necrosis factor (TNF)-α secretion. From a microarray, real-time polymerase chain reaction (PCR), and cytokine array studies, we showed ...[more]

PMID: 20675368

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Project description:BACKGROUND: The phosphodiesterase 4D (PDE4D) gene was reported as a susceptibility gene to stroke. The genetic effect might be attributed to its role in modulating the atherogenic process in the carotid arteries. Using carotid intima-media thickness (IMT) and plaque index as phenotypes, the present study sought to determine the influence of this gene on subclinical atherosclerosis. METHODS: Carotid ultrasonography was performed on 1013 stroke-free subjects who participated in the health screening programs (age 52.6 +/- 12.2; 47.6% men). Genotype distribution was compared among the high-risk (plaque index > or = 4), low-risk (index = 1-3), and reference (index = 0) groups. We analyzed continuous IMT data and further dichotomized IMT data using mean plus one standard deviation as the cutoff level. Because the plaque prevalence and IMT values displayed a notable difference between men and women, we carried out sex-specific analyses in addition to analyzing the overall data. Rs702553 at the PDE4D gene was selected because it conferred a risk for young stroke in our previous report. Previous young stroke data (190 cases and 211 controls) with an additional 532 control subjects without ultrasonic data were shown as a cross-validation for the genetic effect. RESULTS: In the overall analyses, the rare homozygote of rs702553 led to an OR of 3.1 (p = 0.034) for a plaque index > or = 4. When subjects were stratified by sex, the genetic effect was only evident in men but not in women. Comparing male subjects with plaque index > or = 4 and those with plaque index = 0, the TT genotype was over-represented (27.6% vs. 13.4%, p = 0.008). For dichotomized IMT data in men, the TT genotype had an OR of 2.1 (p = 0.032) for a thicker IMT at the common carotid artery compared with the (AA + AT) genotypes. In women, neither IMT nor plaque index was associated with rs702553. Similarly, SNP rs702553 was only significant in young stroke men (OR = 1.8, p = 0.025) but not in women (p = 0.27). CONCLUSIONS: The present study demonstrates a sex-differential effect of PDE4D on IMT, plaque index and stroke, which highlights its influence on various aspects of atherogenesis.

Dataset Information

Tilapia hepcidin 2-3 peptide modulates lipopolysaccharide-induced cytokines and inhibits tumor necrosis factor-alpha through cyclooxygenase-2 and phosphodiesterase 4D.

Publications

Tilapia hepcidin 2-3 peptide modulates lipopolysaccharide-induced cytokines and inhibits tumor necrosis factor-alpha through cyclooxygenase-2 and phosphodiesterase 4D.

Similar Datasets

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