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?-defensin 2 ameliorates lung injury caused by Pseudomonas infection and regulates proinflammatory and anti-inflammatory cytokines in rat.

ABSTRACT: An important member of the defensin family, ?-defensin 2, is believed to play an important role in defense against foreign pathogens. In the present study, we constructed lentiviral vectors to express and knockdown ?-defensin 2 in rat lungs. The results showed that the infection of ?-defensin 2 overexpression lentivirus and ?-defensin 2 shRNA effectively increased and suppressed the expression of ?-defensin 2 in rat lung, respectively. The overexpression of ?-defensin 2 mediated by the lentiviral vector protected lung from infection of Pseudomonas aeruginosa, but shRNA targeting ?-defensin 2 aggregated the damage of lung. In addition, we also found that ?-defensin 2 overexpression increased basal expression of anti-inflammatory cytokine such as IL-4, IL-10 and IL-13 and decreased levels of proinflammatory cytokines which include IL-1?, IL-1?, IL-5, IL-6, IL-8, IL-18, and TNF-?. Moreover, in the process of cytokine regulation, NF-?B pathway may be involved. Taken together, these data suggest that ?-defensin 2 has protective effects against infection of Pseudomonas aeruginosa in rat and plays a role in inflammatory regulation by adjusting cytokine levels.

SUBMITTER: Shen Z

PROVIDER: S-EPMC4159799 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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β-defensin 2 ameliorates lung injury caused by Pseudomonas infection and regulates proinflammatory and anti-inflammatory cytokines in rat.

Shen Zhenwei Z Fang Lu L Zhao Liming L Lei Han H

International journal of molecular sciences 20140730 8

An important member of the defensin family, β-defensin 2, is believed to play an important role in defense against foreign pathogens. In the present study, we constructed lentiviral vectors to express and knockdown β-defensin 2 in rat lungs. The results showed that the infection of β-defensin 2 overexpression lentivirus and β-defensin 2 shRNA effectively increased and suppressed the expression of β-defensin 2 in rat lung, respectively. The overexpression of β-defensin 2 mediated by the lentivira ...[more]

PMID: 25079443

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Project description:Our previous work indicated that the subfornical organ (SFO) is an important brain sensor of blood-borne proinflammatory cytokines, mediating their central effects on autonomic and cardiovascular function. However, the mechanisms by which SFO mediates the central effects of circulating proinflammatory cytokines remain unclear. We hypothesized that proinflammatory cytokines act within the SFO to upregulate the expression of excitatory and inflammatory mediators that drive sympathetic nerve activity. In urethane-anesthetized Sprague-Dawley rats, direct microinjection of tumor necrosis factor (TNF)-? (25 ng) or interleukin (IL)-1? (25 ng) into SFO increased mean blood pressure, heart rate, and renal sympathetic nerve activity within 15 to 20 minutes, mimicking the response to systemically administered proinflammatory cytokines. Pretreatment of SFO with microinjections of the angiotensin II type-1 receptor blocker losartan (1 ?g), angiotensin-converting enzyme inhibitor captopril (1 ?g) or cyclooxygenase-2 inhibitor NS-398 (2 ?g) attenuated those responses. Four hours after the SFO microinjection of TNF-? (25 ng) or IL-1? (25 ng), mRNA for angiotensin-converting enzyme, angiotensin II type-1 receptor, TNF-? and the p55 TNF-? receptor, IL-1? and the IL-1R receptor, and cyclooxygenase-2 had increased in SFO, and mRNA for angiotensin-converting enzyme, angiotensin II type-1 receptor, and cyclooxygenase-2 had increased downstream in the hypothalamic paraventricular nucleus. Confocal immunofluorescent images revealed that immunoreactivity for the p55 TNF-? receptor and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, colocalized with angiotensin-converting enzyme, angiotensin II type-1 receptor-like, cyclooxygenase-2, and prostaglandin E2 EP3 receptor immunoreactivity in SFO neurons. These data suggest that proinflammatory cytokines act within the SFO to upregulate the expression of inflammatory and excitatory mediators that drive sympathetic excitation.

Project description:ObjectivePeriploca forrestii Schltr has been used as a Chinese folk medicine for the treatment of rheumatism, arthralgia and fractures. However, the anti-arthritic activity of Periploca forrestii saponin (PFS) and the active compound has still not been revealed. This study aimed to investigate the protective effects and mechanisms of PFS on collagen type II (CII) collagen-induced arthritis (CIA) mice. We sought to investigate whether PFS and Periplocin could regulate osteoclastogenesis, and if so, further investigation on its mechanism of action.MethodsArthritis was induced in female BALB/c mice by CIA method. PFS was administered at a dose of 50 mg/kg body weight once daily for five weeks. The effects of treatment in mice were assessed by histological and biochemical evaluation in sera and paws. Anti-osteoclastogenic action of PFS and Periplocin was identified using an osteoclast formation model induced by RANKL.ResultsPFS ameliorated paw erythema and swelling, inhibited bone erosion in ankle joint histopathological examination. PFS treatment resulted in decreased IgG2a, and increased IgG1 levels in the serum of CIA mice. Decreased TNF-α, and increased interleukin (IL)-4 and IL-22 levels were also found in PFS-treated mice. PFS inhibited the I-κBα phosphorylation, blocked nuclear factor (NF)-κB/p65 phosphorylation and abrogated AP-1/c-Fos activity. PFS downregulated toll-like receptor (TLR) 4, STAT3 and MMP-9 expression in CIA mice and RANKL-induced osteoclastogenesis. PFS and Periplocin inhibited RANKL-induced osteoclast formation in a dose dependent manner within nongrowth inhibitory concentration, and PFS decreased osteoclastogenesis-related marker expression, including cathepsin K and MMP-9.ConclusionThis study revealed that the protective mechanism of PFS on CIA was associated with regulatory effects on proinflammatory factors and further on the crosstalk between NF-κB and c-Fos/AP-1 in vivo and in vitro. Therefore, PFS is a promising therapeutic alternative for the treatment of RA, evidencing the need to conduct further studies that can identify their active components in treating and preventing RA.

Dataset Information

?-defensin 2 ameliorates lung injury caused by Pseudomonas infection and regulates proinflammatory and anti-inflammatory cytokines in rat.

Publications

β-defensin 2 ameliorates lung injury caused by Pseudomonas infection and regulates proinflammatory and anti-inflammatory cytokines in rat.

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