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Protective role of interleukin-10 in ozone-induced pulmonary inflammation.

ABSTRACT: The mechanisms underlying ozone (O?)-induced pulmonary inflammation remain unclear. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators.We investigated the molecular mechanisms underlying interleuken-10 (IL-10)-mediated attenuation of O?-induced pulmonary inflammation in mice.Il10-deficient (Il10(-/-)) and wild-type (Il10(+/+)) mice were exposed to 0.3 ppm O? or filtered air for 24, 48, or 72 hr. Immediately after exposure, differential cell counts and total protein (a marker of lung permeability) were assessed from bronchoalveolar lavage fluid (BALF). mRNA and protein levels of cellular mediators were determined from lung homogenates. We also used global mRNA expression analyses of lung tissue with Ingenuity Pathway Analysis to identify patterns of gene expression through which IL-10 modifies O?-induced inflammation.Mean numbers of BALF polymorphonuclear leukocytes (PMNs) were significantly greater in Il10(-/-) mice than in Il10(+/+) mice after exposure to O? at all time points tested. O?-enhanced nuclear NF-?B translocation was elevated in the lungs of Il10(-/-) compared with Il10(+/+) mice. Gene expression analyses revealed several IL-10-dependent and O?-dependent mediators, including macrophage inflammatory protein 2, cathepsin E, and serum amyloid A3.Results indicate that IL-10 protects against O?-induced pulmonary neutrophilic inflammation and cell proliferation. Moreover, gene expression analyses identified three response pathways and several genetic targets through which IL-10 may modulate the innate and adaptive immune response. These novel mechanisms of protection against the pathogenesis of O?-induced pulmonary inflammation may also provide potential therapeutic targets to protect susceptible individuals.

SUBMITTER: Backus GS

PROVIDER: S-EPMC3002191 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Protective role of interleukin-10 in ozone-induced pulmonary inflammation.

Backus Gillian S GS Howden Reuben R Fostel Jennifer J Bauer Alison K AK Cho Hye-Youn HY Marzec Jacqui J Peden David B DB Kleeberger Steven R SR

Environmental health perspectives 20100908 12

<h4>Background</h4>The mechanisms underlying ozone (O₃)-induced pulmonary inflammation remain unclear. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators.<h4>Objectives</h4>We investigated the molecular mechanisms underlying interleuken-10 (IL-10)-mediated attenuation of O₃-induced pulmonary inflammation in mice.<h4>Methods</h4>Il10-deficient (Il10(-/-)) and wild-type (Il10(+/+)) mice were exposed to 0.3 ppm O₃ or filtered air for 24, 48, or 7 ...[more]

PMID: 20826374

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Project description:Background: The mechanisms underlying ozone (O3)-induced pulmonary inflammation remain unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators. Objectives: The current study investigated the molecular mechanisms underlying IL-10-mediated attenuation of O3-induced pulmonary inflammation in mice. Methods: Il10-deficient (Il10-/-) and wild type (Il10+/+) mice were exposed to 0.3-ppm O3 or filtered air for 24, 48 or 72 hr. Immediately following exposure, differential cell counts, and total protein (a marker of lung permeability) were assessed from bronchoalveolar lavage fluid (BALF). mRNA and protein levels of cellular mediators were determined from lung homogenates. We also utilized global mRNA expression analyses of lung tissue with Ingenuity Pathway Analyses (IPA) to identify patterns of gene expression through which IL-10 modifies O3-induced inflammation. Results: Mean numbers of BALF polymorphonuclear leukocytes (PMNs) were significantly greater in Il10-/- mice than in Il10+/+ mice after exposure to O3 at all time points tested. O3-enhanced nuclear NF-kB translocation was elevated in the lungs of Il10-/- compared to Il10+/+ mice. Gene expression analyses revealed several key IL-10 and O3-dependent mediators, including IL-6, MIP-2, IL-1 and CD86. Conclusions: Results indicated that IL-10 protects against O3-induced pulmonary neutrophilic inflammation and cell proliferation. Moreover, gene expression analyses identified three response pathways and several novel genetic targets (e.g. Ccr1, Socs3, Il33, Hat1, and Gale) through which IL10 may modulate the innate and adaptive immune response. These novel mechanisms of protection against the pathogenesis of O3-induced pulmonary inflammation may also provide potential therapeutic targets to protect susceptible individuals. PARALLEL study design with 26 samples. Biological replicates: 2 to 3 replicates per group with wild type air exposed animals as controls for each time point (24, 48, 72 hours). Time-Course, Dose-Response, Strain comparison

Project description:BACKGROUND:Interleukin-33 is released in the airways following acute ozone exposure and has the ability to cause airway hyperresponsiveness, a defining feature of asthma. Ozone causes greater airway hyperresponsiveness in male than female mice. Moreover, sex differences in the gut microbiome account for sex differences in this response to ozone. The purpose of this study was to determine whether there were sex differences in the role of interleukin-33 in ozone-induced airway hyperresponsiveness and to examine the role of the microbiome in these events. METHODS:Wildtype mice and mice genetically deficient in ST2, the interleukin-33 receptor, were housed from weaning with either other mice of the same genotype and sex, or with mice of the same sex but opposite genotype. At 15?weeks of age, fecal pellets were harvested for 16S rRNA sequencing and the mice were then exposed to air or ozone. Airway responsiveness was measured and a bronchoalveolar lavage was performed 24?h after exposure. RESULTS:In same-housed mice, ozone-induced airway hyperresponsiveness was greater in male than female wildtype mice. ST2 deficiency reduced ozone-induced airway hyperresponsiveness in male but not female mice and abolished sex differences in the response to ozone. However, sex differences in the role of interleukin-33 were unrelated to type 2 cytokine release: ozone-induced increases in bronchoalveolar lavage interleukin-5 were greater in females than males and ST2 deficiency virtually abolished interleukin-5 in both sexes. Since gut microbiota contribute to sex differences in ozone-induced airway hyperresponsiveness, we examined the role of the microbiome in these ST2-dependent sex differences. To do so, we cohoused wildtype and ST2 deficient mice, a situation that allows for transfer of microbiota among cage-mates. Cohousing altered the gut microbial community structure, as indicated by 16S rRNA gene sequencing of fecal DNA and reversed the effect of ST2 deficiency on pulmonary responses to ozone in male mice. CONCLUSIONS:The data indicate that the interleukin-33 /ST2 pathway contributes to ozone-induced airway hyperresponsiveness in male mice and suggest that the role of interleukin-33 is mediated at the level of the gut microbiome.

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Protective role of interleukin-10 in ozone-induced pulmonary inflammation.

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Protective role of interleukin-10 in ozone-induced pulmonary inflammation.

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