Dataset Information

Clara cell 10-kDa protein inhibits T(H)17 responses through modulating dendritic cells in the setting of allergic rhinitis.

ABSTRACT:

Background

T(H)17 responses have recently been implicated to play a role in allergic airway diseases, but their local expression in the setting of allergic rhinitis (AR) and their regulation in allergic airway diseases remain unclear.

Objective

We sought to investigate the regulatory role of Clara cell 10-kDa protein (CC10), an endogenous regulator of airway inflammation, on T(H)17 responses in the setting of AR.

Methods

Wild-type and homozygous CC10-null mice were used to establish an ovalbumin (OVA)-induced AR model. Human recombinant CC10 was given during sensitization or challenge. T(H)17 responses in human subjects and mice were examined by using flow cytometry, quantitative RT-PCR assay, immunohistochemistry, and ELISA. The direct effect of CC10 on T(H)17 cells and CD11c(+) dendritic cells (DCs) was studied by means of cell culture. Adoptive transfer was used to examine the influence of CC10-conditioned DCs on airway inflammation. The regulatory effect of CC10 on the expression of the CCL20 gene was tested by using the BEAS-2B cell line.

Results

Compared with those of control subjects, T(H)17 responses were enhanced in the nasal mucosa of patients with AR. CC10-null mice with AR showed enhanced T(H)17 responses, and CC10 treatment significantly decreased T(H)17 responses. CC10 had no direct effect on in vitro T(H)17 cell differentiation. CC10 could significantly decrease the expression of OX40 ligand, IL-23, and IL-6 but enhance CD86 and TGF-? expression in DCs. Importantly, CC10 was able to inhibit T(H)17 cell polarization in the presence of OVA-pulsed DCs. CC10 pretreatment inhibited T(H)17 responses elicited by adoptive transfer of OVA-pulsed DCs. Furthermore, CC10 decreased the expression of CCL20 in BEAS-2B cells induced by inflammatory cytokines.

Conclusion

T(H)17 responses are enhanced in patients with AR, and CC10 inhibits T(H)17 responses through modulation of the function of DCs.

SUBMITTER: Liu Y

PROVIDER: S-EPMC3633083 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Publications

Clara cell 10-kDa protein inhibits T(H)17 responses through modulating dendritic cells in the setting of allergic rhinitis.

Liu Yang Y Yu Hai-Jing HJ Wang Nan N Zhang Ya-Na YN Huang Shau-Ku SK Cui Yong-Hua YH Liu Zheng Z

The Journal of allergy and clinical immunology 20121228 2

<h4>Background</h4>T(H)17 responses have recently been implicated to play a role in allergic airway diseases, but their local expression in the setting of allergic rhinitis (AR) and their regulation in allergic airway diseases remain unclear.<h4>Objective</h4>We sought to investigate the regulatory role of Clara cell 10-kDa protein (CC10), an endogenous regulator of airway inflammation, on T(H)17 responses in the setting of AR.<h4>Methods</h4>Wild-type and homozygous CC10-null mice were used to ...[more]

PMID: 23273949

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Project description:Osteopontin (OPN) is a multifunctional protein that has recently been linked to allergic diseases. Clara cell 10 kDa protein (CC10) is another protein linked to allergy, and has been suggested to have an inhibitory role in inflammatory airway diseases. At this time, it is not known whether OPN is involved in allergic rhinitis (AR) or if there is any association between CC10 and OPN in AR.To study the expression of OPN and its potential association with CC10 in AR.The expression of CC10 and OPN in nasal mucosa of AR patients was investigated. AR animal models were established by using wild-type and CC10-knockout mice. In some experiments, human recombinant CC10 protein was given to AR mice during either sensitization or challenge. The phenotypic changes were examined by histology and real-time RT-PCR. The direct effect of CC10 on the OPN expression in spleen mononuclear cells and on the OPN-induced inflammatory cytokine expression in BEAS-2B cells was measured through in vitro cell culture.OPN expression was up-regulated, with a concomitant down-regulation of CC10, in AR patients, showing a significant negative correlation between their expression. Compared with control mice sensitized with PBS, the OPN expression was significantly increased in AR mice; such an increase was more prominent in CC10-knockout mice, compared with wild-type. Administration of CC10 during both sensitization and challenge could markedly ameliorate Th2-skewed inflammation and OPN expression in nasal mucosa. CC10 administration at the sensitization phase could also reduce spleen OPN expression. The in vitro study showed that CC10 directly down-regulated the OPN expression in spleen mononuclear cells stimulated with OVA and suppressed the OPN-induced expression of Th2 cytokines and pro-inflammatory cytokines in BEAS-2B cells.In the context of allergic airway responses, CC10 can inhibit OPN expression and suppress the Th2-promoting function of OPN, resulting in CC10's inhibitory biological effects.

Project description:Background: Fulminant hepatitis (FH) is a serious threat to human life, accompanied by massive and rapid necroinflammation. Kupffer cells, the major immune cell population involved in innate immune responses, are considered to be central for FH. Fibrinogen-like protein 2 (Fgl2) is a pro-coagulant protein that is substantially induced in macrophages upon viral infection, and Fgl2 depletion represses murine hepatitis virus strain 3 (MHV-3) infection. Clara cell 10 kDa (CC10) protein is a secretory protein with anti-inflammatory properties in allergic rhinitis and asthma. However, its mechanisms of action and pathogenic roles in other disease are still unclear. In this study, we aimed to determine the role of CC10 in FH and the regulation of Fgl2 by CC10. Methods: A mouse FH model was established by peritoneal injection of MHV-3. The mice received CC10 protein through tail vein injection before viral infection. Survival rate, liver function, liver histology, fibrin deposition, and necrosis were examined. The regulatory effect of CC10 on Fgl2 expression was investigated using THP-1 cells and mouse peritoneal macrophages in vitro. Results: In the mouse FH model induced by MHV-3, the survival rate increased from 0 to 12.5% in the CC10 group compared to that in the saline-only control group. Meanwhile, the levels of ALT and AST in serum were significantly decreased and liver damage was reduced. Furthermore, hepatic Fgl2, TNF-α, and IL-1β expression was obviously downregulated together with fibrin deposition, and hepatocyte apoptosis was reduced after administration of CC10 protein. In vitro, CC10 was found to significantly inhibit the expression of Fgl2 in IFN-γ-treated THP-1 cells and MHV-3-infected mouse peritoneal macrophages by western blot and real-time PCR. However, there was no direct interaction between CC10 and Fgl2 as shown by co-immunoprecipitation. Microarray investigations suggested that HMG-box transcription factor 1 (HBP1) was significantly low in CC10-treated and IFN-γ-primed THP-1 cells. HBP1-siRNA treatment abrogated the inhibitory effect of CC10 on Fgl2 expression in Human Umbilical Vein Endothelial cells (HUVECs). Conclusion:CC10 protects against MHV-3-induced FH via suppression of Fgl2 expression in macrophages. Such effects may be mediated by the transcription factor HBP1.

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Dataset Information

Clara cell 10-kDa protein inhibits T(H)17 responses through modulating dendritic cells in the setting of allergic rhinitis.

Background

Objective

Methods

Results

Conclusion

Publications

Clara cell 10-kDa protein inhibits T(H)17 responses through modulating dendritic cells in the setting of allergic rhinitis.

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