TLRs are a family of receptors that mediate immune system pathogen recognition. In the respiratory system, TLR activation has both beneficial and deleterious effects in asthma. For example, clinical data indicate that TLR6 activation exerts protective effects in asthma. Here, we explored the mechanism or mechanisms through which TLR6 mediates this effect using mouse models of Aspergillus fumigatus-induced and house dust mite antigen-induced (HDM antigen-induced) chronic asthma. Tlr6 -/-mice with fungal-or HDM antigen-induced asthma exhibited substantially increased airway hyperresponsiveness, inflammation, and remodeling compared with WT asthmatic groups. Surprisingly, whole-lung levels of IL-23 and IL-17 were markedly lower in Tlr6 -/-versus WT asthmatic mice. Tlr6 -/-DCs generated less IL-23 upon activation with lipopolysaccharide, zymosan, or curdlan. Impaired IL-23 generation in Tlr6 -/-mice also corresponded with lower levels of expression of the pathogen-recognition receptor dectin-1 and expansion of Th17 cells both in vivo and in vitro.

IL-33 and its soluble receptor and cell-associated receptor (ST2L) are all increased in clinical and experimental asthma. The present study addressed the hypothesis that ST2L impairs the therapeutic effects of CpG in a fungal model of asthma. C57BL/6 mice were sensitized to Aspergillus fumigatus and challenged via i.t. instillation with live A. fumigatus conidia. Mice were treated with IgG alone, anti-ST2L monoclonal antibody (mAb) alone, CpG alone, IgG plus CpG, or anti-ST2L mAb plus CpG every other day from day 14 to day 28 and investigated on day 28 after conidia. Lung ST2L and toll-like receptor 9 protein expression levels concomitantly increased in a time-dependent manner during fungal asthma. Therapeutic blockade of ST2L with an mAb attenuated key pathological features of this model. At subtherapeutic doses, neither anti-ST2L mAb nor CpG alone affected fungal asthma severity. However, airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention were markedly reduced in asthmatic mice treated with the combination of both. Whole lung CXCL9 levels were significantly elevated in the combination group but not in the controls. Furthermore, in asthmatic mice treated with the combination therapy, dendritic cells generated significantly greater IL-12p70 with CpG in vitro compared with control dendritic cells. The combination of anti-ST2L mAb with CpG significantly attenuated experimental asthma, suggesting that targeting ST2L might enhance the therapeutic efficacy of CpG during allergic inflammation.

No abstract

Tumor necrosis factor-alpha (TNF-alpha) is a mediator of inflammation in human and animal renal disease. Pentoxiphylline (PTX) is an inhibitor of TNF-alpha. In this study we examined the effects of PTX on TNF-alpha, proteinuria, nitrite production, and apoptosis in an experimental model of Adriamycin (ADR) nephropathy in rats. Rats were divided into four groups: untreated Wistar rats (controls), PTX treatment alone, ADR treatment alone to induce nephropathy, and ADR treatment followed by PTX. ADR treatment followed by PTX treatment prevented the increase in serum TNF-alpha levels and proteinuria in rats with ADR-nephropathy ( P<0.05). Urine nitrite levels were significantly increased in the ADR-induced nephropathy group and the increase was prevented in the ADR-induced nephropathy group when they also received PTX. The urine nitrite levels were not different between the PTX-treated group and the untreated control rats. PTX prevented the rise of serum TNF-alpha in ADR nephropathy rats and a decrease in proteinuria, urine nitrite, and apoptosis in the renal tissue. These findings suggest a beneficial anti-inflammatory effect of PTX.

No abstract

Growth arrest-specific gene (Gas)6 is a secreted vitamin K-dependent protein with pleiotropic effects via activation of receptor tyrosine kinase Tyro3, Axl, and Mertk receptors, but little is known about its role in allergic airway disease. We investigated the role of Gas6 in the development of fungal allergic airway disease in mice. The immune response was evaluated in Gas6-deficient (Gas6-/-) and wild-type (WT) mice and in recombinant Gas6-treated WT mice during Aspergillus fumigatus-induced allergic airway disease. Gas6 plasma levels were significantly elevated in adult clinical asthma of all severities compared with subjects without asthma. In a murine model of fungal allergic airway disease, increased protein expression of Axl and Mertk were observed in the lung. Airway hyperresponsiveness (AHR), whole lung Th2 cytokine levels, goblet cell metaplasia, and peribronchial fibrosis were ameliorated in Gas6-/- mice compared with WT mice with fungal allergic airway disease. Intranasal Gas6 administration into WT mice had a divergent effect on airway inflammation and AHR. Specifically, a total dose of 2 μg of exogenous Gas6 (i.e., low dose) significantly increased whole lung Th2 cytokine levels and subsequent AHR, whereas a total dose of 7 μg of exogenous Gas6 (i.e., high dose) significantly suppressed Th1 and Th2 cytokines and AHR compared with appropriate control groups. Mechanistically, Gas6 promoted Th2 activation via its highest affinity receptor Axl expressed by myeloid DCs. Intranasal administration of Gas6 consistently exacerbated airway remodeling compared with control WT groups. These results demonstrate that Gas6 enhances several features of fungal allergic airway disease.

No abstract

The effect of urinary bladder inflammation on the activity of a bladder-derived relaxant factor in the coaxial bioassay system was examined. Bladder inflammation was induced by intraperitoneal (i.p.) cyclophosphamide or intravesical lipopolysaccharide (LPS) injection to male rats. In precontracted rat anococcygeus muscle that was placed within rat bladder (coaxial bioassay system), acetylcholine induced a relaxation response, which was not altered by the denudation of urothelium or incubation with indomethacin and N(G)-methyl-L-arginine. Acetylcholine-induced relaxation was significantly attenuated, when bladders were removed from cyclophosphamide- and LPS-pretreated group of rats and were used with intact urothelium in the coaxial bioassay system. However, the impairment acetylcholine response in both pretreatment groups was not observed after denudation of the bladder urothelium. These results showed that bladder inflammation did not alter the synthesis and/or release of this bladder-derived relaxant factor, which is neither a cyclooxygenase product nor nitric oxide, but restricted its demonstration by coaxial bioassay assembly probably due to inflammation-induced mucosal oedema.