IL-4Rα-responsive smooth muscle cells contribute to initiation of TH2 immunity and pulmonary pathology in Nippostrongylus brasiliensis infections.

Nippostrongylus brasiliensis infections generate pulmonary pathologies that can be associated with strong T(H)2 polarization of the host's immune response. We present data demonstrating N. brasiliensis-driven airway mucus production to be dependent on smooth muscle cell interleukin 4 receptor-α (IL-4Rα) responsiveness. At days 7 and 10 post infection (PI), significant airway mucus production was found in IL-4Rα(-/lox) control mice, whereas global knockout (IL-4Rα(-/-)) and smooth muscle-specific IL-4Rα-deficient mice (SM-MHC(Cre) IL-4Rα(-/lox)) showed reduced airway mucus responses. Furthermore, interleukin (IL)-13 and IL-5 cytokine production in SM-MHC(Cre) IL-4Rα(-/lox) mice was impaired along with a transient reduction in T-cell numbers in the lung. In vitro treatment of smooth muscle cells with secreted N. brasiliensis excretory-secretory antigen (NES) induced IL-6 production. Decreased protein kinase C (PKC)-dependent smooth muscle cell proliferation associated with cell cycle arrest was found in cells stimulated with NES. Together, these data demonstrate that both IL-4Rα and NES-driven responses by smooth muscle cells make important contributions in initiating T(H)2 responses against N. brasiliensis infections.

Functional analysis of the 5' regulatory region of the 5-aminolevulinate synthase (ALAS1) gene in response to estrogen.

Genetic defects in the heme synthesis enzymes lead to a group of heterogeneous disorders termed the porphyrias. Numerous factors influence the clinical expression of porphyrias, primarily by altering the rate of heme synthesis. To date, no genotype-phenotype correlation has been made to explain the variable penetrance observed in variegate porphyria (VP) and other acute hepatic porphyrias. As first and rate determining gene in the heme pathway, 5-aminolevulinate synthase-1 (ALAS1), appears to be an ideal candidate modifier. Previous studies established critical mechanisms for ALAS1 regulation and a direct transcriptional response to drugs by defined drug-responsive enhancer sequences (ADRES). To identify possible functional variants within the 5' region of ALAS1, selected regulatory regions, including the ADRES elements, were screened by DNA sequencing analysis in 26 VP patients heterozygous for the causative R59W mutation in the protoporphyrinogen oxidase (PPOX) gene. Two novel variants, -853C>T and -1253T>A were identified. In silico analyses indicated that the -853C>T transition is located immediately 5' to a half-palindromic putative estrogen receptor binding site. Co-transfection experiments with an estrogen receptor-alpha (ERalpha) expression vector in HepG2 cells, suggest that this region mediates an increased transcriptional response in the presence of estrogen (E2) and ERalpha. The wild-type -853C/-1253T allele induced a 47% increase in transcription, while the -853T/-1253A double mutant allele showed a 35% increase in transcription compared to expression in the absence of E2. The highest induction was observed for the mutant -853T/1253T allele that generated an increase of 66%. We conclude that the -853T variant functions as an enhancer in the presence of estrogen and speculates that the -1253A variant reduces transcription activity.

Uterine actinomycosis. A case report and review.

Current literature documents an association between intra-uterine contraceptive usage and genital tract colonization or infection with actinomycosis. Uterine involvement, however, is extremely rate. A case of severe pelvic infection with uterine perforation due to an actinomycosis fistula as confirmed by tissue is presented. The condition of actinomycosis is reviewed with special attention to involvement of the female pelvic organs and the difficulties in diagnosis.