IL-11 and IL-11 receptor (R)alpha are induced by Th2 cytokines. However, the role(s) of endogenous IL-11 in antigen-induced Th2 inflammation has not been fully defined. We hypothesized that IL-11, signaling via IL-11Ralpha, plays an important role in aeroallergen-induced Th2 inflammation and mucus metaplasia. To test this hypothesis, we compared the responses induced by the aeroallergen ovalbumin (OVA) in wild-type (WT) and IL-11Ralpha-null mutant mice. We also generated and defined the effects of an antagonistic IL-11 mutein on pulmonary Th2 responses. Increased levels of IgE, eosinophilic tissue and bronchoalveolar lavage (BAL) inflammation, IL-13 production, and increased mucus production and secretion were noted in OVA-sensitized and -challenged WT mice. These responses were at least partially IL-11 dependent because each was decreased in mice with null mutations of IL-11Ralpha. Importantly, the administration of the IL-11 mutein to OVA-sensitized mice before aerosol antigen challenge also caused a significant decrease in OVA-induced inflammation, mucus responses, and IL-13 production. Intraperitoneal administration of the mutein to lung-specific IL-13-overexpressing transgenic mice also reduced BAL inflammation and airway mucus elaboration. These studies demonstrate that endogenous IL-11R signaling plays an important role in antigen-induced sensitization, eosinophilic inflammation, and airway mucus production. They also demonstrate that Th2 and IL-13 responses can be regulated by interventions that manipulate IL-11 signaling in the murine lung.

An infant with failure to thrive, persistent hyponatremia and episodic vomiting and diarrhea was admitted to hospital at 9 months of age, and the diagnosis of type II aldosterone synthase deficiency was confirmed by plasma and urinary steroid determinations. The entire coding sequence of the aldosterone synthase gene (CYP11B2) was determined (both strands) in the affected infant, an unaffected sibling, and both parents. An exon 3 mutation (C554T, leading to amino acid T185I) was found in the father and both siblings, and an exon 9 mutation (A1492G, leading to T498A) was found in the affected infant and the mother. Expression of the mutant sequences in COS cells showed steroidogenic patterns typical of aldosterone synthase type II deficiency, including very low levels of aldosterone synthesis (< or =0.5% of wild-type enzyme) consistent with the low aldosterone levels in the patient's plasma. Both mutations in this compound heterozygote localize to the beta 3-sheet in the cytochrome P450 enzyme structure, as does the previously characterized R181W mutation. This region of the enzyme is not part of the putative structural core, but mutations to this region suggest that it is important for conferring the unique ability of aldosterone synthase to catalyze efficient oxygenation of the C(18) carbon of steroid substrates.

No abstract

No abstract