BackgroundAsthma is a chronic inflammatory disease of the airway that is characterized by a Th2-type of immune response with increasing evidence for involvement of Th17 cells. The role of IL-6 in promoting effector T cell subsets suggest that IL-6 may play a functional role in asthma. Classically IL-6 has been viewed as an inflammatory marker, along with TNFα and IL-1β, rather than as regulatory cytokine.ObjectiveTo investigate the potential relationship between IL-6 and other proinflammatory cytokines, Th2/Th17 cytokines and lung function in allergic asthma, and thus evaluate the potential role of IL-6 in this disease.MethodsCytokine levels in induced sputum and lung function were measured in 16 healthy control and 18 mild-moderate allergic asthmatic subjects.ResultsThe levels of the proinflammatory biomarkers TNFα and IL-1β were not different between the control and asthmatic group. In contrast, IL-6 levels were specifically elevated in asthmatic subjects compared with healthy controls (p < 0.01). Hierarchical regression analysis in the total study cohort indicates that the relationship between asthma and lung function could be mediated by IL-6. Among Th2 cytokines only IL-13 (p < 0.05) was also elevated in the asthmatic group, and positively correlated with IL-6 levels (rS = 0.53, p < 0.05).ConclusionsIn mild-moderate asthma, IL-6 dissociates from other proinflammatory biomarkers, but correlates with IL-13 levels. Furthermore, IL-6 may contribute to impaired lung function in allergic asthma.

We have directly linked production of a single virulence factor in P. aeruginosa with effects on lung function, and demonstrated that the inhibitor miltefosine protects lung function from PlcHR-dependent surfactant dysfunction.

BackgroundNitrogen dioxide (NO2) is an air pollutant associated with poor respiratory health, asthma exacerbation, and an increased likelihood of inhalational allergies. NO2 is also produced endogenously in the lung during acute inflammatory responses. NO2 can function as an adjuvant, allowing for allergic sensitization to an innocuous inhaled antigen and the generation of an antigen-specific Th2 immune response manifesting in an allergic asthma phenotype. As CD11c+ antigen presenting cells are considered critical for naïve T cell activation, we investigated the role of CD11c+ cells in NO2-promoted allergic sensitization.MethodsWe systemically depleted CD11c+ cells from transgenic mice expressing a simian diphtheria toxin (DT) receptor under of control of the CD11c promoter by administration of DT. Mice were then exposed to 15 ppm NO2 followed by aerosolized ovalbumin to promote allergic sensitization to ovalbumin and were studied after subsequent inhaled ovalbumin challenges for manifestation of allergic airway disease. In addition, pulmonary CD11c+ cells from wildtype mice were studied after exposure to NO2 and ovalbumin for cellular phenotype by flow cytometry and in vitro cytokine production.ResultsTransient depletion of CD11c+ cells during sensitization attenuated airway eosinophilia during allergen challenge and reduced Th2 and Th17 cytokine production. Lung CD11c+ cells from wildtype mice exhibited a significant increase in MHCII, CD40, and OX40L expression 2 hours following NO2 exposure. By 48 hours, CD11c+MHCII+ DCs within the mediastinal lymph node (MLN) expressed maturation markers, including CD80, CD86, and OX40L. CD11c+CD11b- and CD11c+CD11b+ pulmonary cells exposed to NO2 in vivo increased uptake of antigen 2 hours post exposure, with increased ova-Alexa 647+ CD11c+MHCII+ DCs present in MLN from NO2-exposed mice by 48 hours. Co-cultures of ova-specific CD4+ T cells from naïve mice and CD11c+ pulmonary cells from NO2-exposed mice produced IL-1, IL-12p70, and IL-6 in vitro and augmented antigen-induced IL-5 production.ConclusionsCD11c+ cells are critical for NO2-promoted allergic sensitization. NO2 exposure causes pulmonary CD11c+ cells to acquire a phenotype capable of increased antigen uptake, migration to the draining lymph node, expression of MHCII and co-stimulatory molecules required to activate naïve T cells, and secretion of polarizing cytokines to shape a Th2/Th17 response.

In addition to immune cells, airway epithelial cells can contribute to and shape the immune response in the lung by secreting specific cytokines. IL-6 is a key factor in determining the effector fate of CD4(+) T cells. Here we show that under basal conditions, the IL-6 gene is already highly expressed in lung epithelial cells, but not in immune cells resident in the lung. However, upon exposure of the lungs to fungal allergens, the direct contact of β-glucans present in the fungus cell wall with lung epithelial cells is sufficient to trigger the rapid synthesis and secretion of IL-6 protein. This posttranscriptional regulation of IL-6 in response to fungal extracts is mediated by the p38 mitogen-activated protein kinase pathway. The inhalation of β-glucans with a nonallergenic antigen is sufficient to provide an adjuvant effect that leads to mucous hyperplasia in the airways. Thus, β-glucans may constitute a common determinant of the fungal and plant-derived allergens responsible for some of the pathological features in allergic asthma.

ABSTRACT:CYP2E1 is widely accepted as the sole form of cytochrome P450 responsible for alcohol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, we previously found that alcohol [ethanol and isopentanol (EIP)] causes increases in APAP hepatotoxicity in Cyp2e1(؊/؊) mice, indicating that CYP2E1 is not essential. Here, using wild-type and Cyp2e1(؊/؊) mice, we investigated the relative roles of CYP2E1 and CYP3A in EIP-mediated increases in APAP hepatotoxicity. We found that EIP-mediated increases in APAP hepatotoxicity occurred at lower APAP doses in wild-type mice (300 mg/kg) than in Cyp2e1(؊/؊) mice (600 mg/kg). Although this result suggests that CYP2E1 has a role in the different susceptibilities of these mouse lines, our findings that EIP-mediated increases in CYP3A activities were greater in wild-type mice compared with Cyp2e1(؊/؊) mice raises the possibility that differential increases in CYP3A may also contribute to the greater APAP sensitivity in EIP-pretreated wild-type mice. At the time of APAP administration, which followed an 11 h withdrawal from the alcohols, alcohol-induced levels of CYP3A were sustained in both mouse lines, whereas CYP2E1 was decreased to constitutive levels in wild-type mice. The CYP3A inhibitor triacetyloleandomycin (TAO) decreased APAP hepatotoxicity in EIP-pretreated wild-type and Cyp2e1(؊/؊) mice. TAO treatment in vivo resulted in inhibition of microsomal CYP3A-catalyzed activity, measured in vitro, with no inhibition of CYP1A2 and CYP2E1 activities. In conclusion, these findings suggest that both CYP3A and CYP2E1 contribute to APAP hepatotoxicity in alcohol-treated mice.Acetaminophen (APAP) is considered to be a relatively safe drug and is widely prescribed and used for its analgesic and antipyretic properties. The first reports of hepatotoxicity in humans resulting from APAP overdose were in 1966 ( Thomson and Prescott, 1966). Today, APAP is a frequent cause of liver failure and the leading cause of death due to accidental and deliberate overdose (for review, see Bromer and Black, 2003). APAP is mainly glucuronidated and sulfated in the liver by phase II metabolic pathways, leading to excretion of the drug. However, APAP is also metabolized by certain forms of cytochromes P450 (P450s) to N-acetyl-p-benzoquinone imine (NAPQI), a highly electrophilic metabolite that is considered to be responsible for triggering the ensuing liver damage. CYP1A2, CYP2E1, and CYP3A are three forms of rat and human P450s active in the conversion of APAP to NAPQI, with CYP2E1 and CYP3A having greater intrinsic activity than CYP1A2 (Patten et al., 1993;Thummel et al., 1993). Reduced glutathione (GSH) reacts with NAPQI, resulting in the inactivation of this reactive metabolite. When GSH levels become depleted, liver damage can occur as a result of the