Interleukin-1 (IL-1) is a proinflammatory cytokine and IL-1 receptor antagonist (IL-1ra) is a natural inhibitor that binds to IL-1 receptor type I without inducing signal transduction. It is suggested that IL-1 is required for allergen-specific T helper type 2 cell activation and the development of airway hyper-responsiveness (AHR), but the immunologic effect of exogenous IL-1ra in allergic asthma remains unclear. To examine the effect of IL-1ra on airway inflammation and immunoeffector cells in allergic asthma, recombinant adenovirus expressing human IL-1ra (Ad-hIL-1ra) was delivered intranasally into ovalbumin (OVA)-immunized mice. Single intranasal administration of Ad-hIL-1ra before airway antigen challenge in OVA-immunized mice significantly decreased the severity of AHR and reduced pulmonary infiltration of eosinophils and neutrophils. Suppression of IL-5 and eotaxin with concomitant enhancement of interferon gamma in bronchoalveolar lavage fluid was also noted in OVA-immunized mice by administration of Ad-hIL-1ra. In addition, histological studies showed that Ad-hIL-1ra was able to decrease OVA-induced peribronchial inflammation. Taken together, our results indicated that administration of Ad-hIL-1ra may have therapeutic potential for the immunomodulatory treatment of allergic asthma.
Plasmacytoid dendritic cells (pDCs) are critical in controlling adaptive immunity, but the mechanisms governing cytokine expression remain incompletely defined. Analogues of prostaglandin (PG)I 2 , such as iloprost, can modulate functions of myeloid dendritic cells, but their involvement in the regulation of human pDCs remains unknown. To this end, the regulatory role of PGI 2 analogues on cytokine expression in pDCs was investigated.Circulating pDCs were magnetically sorted with BDCA-4 cell isolation kits from human peripheral blood mononuclear cells and treated with varying concentrations of iloprost with or without the addition of Toll-like receptor agonists, or an I prostanoid (IP) receptor antagonist, CAY10449. The levels of tumour necrosis factor (TNF)-a, interferon (IFN)-a and interleukin (IL)-10 were measured by ELISA.Iloprost induced IL-10 expression, but suppressed CpG oligodeoxynucleotide-(or imiquimod-) induced TNF-a and IFN-a production in pDCs. This effect was reversed by the addition of CAY10449. Forskolin, a cyclic adenosine monophosphate activator, conferred a similar modulating effect to that noted in iloprost-treated pDCs, although a higher concentration of forskolin was required to exert the same effect.Iloprost enhanced interleukin-10 and suppressed Toll-like receptor-mediated tumour necrosis factor-a and interferon-a production of human plasmacytoid dendritic cells via the I prostanoid receptor and, in part, the cyclic adenosine monophosphate pathway.
Allergic asthma is characterized by airway hyper-responsiveness (AHR) and cellular infiltration of the airway with predominantly eosinophils and Th2 cells. The normal resolution of inflammation in the lung occurs through the regulated removal of unneeded cells by Fas-Fas ligandmediated apoptosis. Fas ligand (FasL) is a member of the tumor necrosis factor family, and when bound to Fas, it induces apoptosis of the cells. To examine the effect of the FasL gene on airway inflammation and immune effector cells in allergic asthma, recombinant adenovirus expressing murine FasL (Ad-FasL) was delivered intratracheally into ovalbumin (OVA)-immunized mice. We found that a single administration of Ad-FasL in OVA-immunized mice significantly alleviated AHR and eosinophilia by inducing the apoptosis of eosinophils and/or reducing eosinophil attractant factors, such as IL-5 and eotaxin levels. The number of infiltrated lymphocytes and Th2 cytokines, including IL-5 and IL-13, decreased in OVA-immunized mice by administration of Ad-FasL. KC and TNF-a production also decreased in AdFasL-treated OVA-immunized mice. These findings indicated that the administration of Ad-FasL to OVA-sensitized mice significantly suppressed pulmonary allergic responses. Although more studies are needed, these results suggested that Ad-FasL might be applied as an alternative therapy for allergic asthma.
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