RESUMO
Lysinuric protein intolerance (LPI) is a recessively inherited aminoaciduria caused by mutations of SLC7A7, the gene encoding y+LAT1 light chain of system y+L for cationic amino acid transport. The pathogenesis of LPI is still unknown. In this study, we have utilized a gene silencing approach in macrophages and airway epithelial cells to investigate whether complications affecting lung and immune system are directly ascribable to the lack of SLC7A7 or, rather, mediated by an abnormal accumulation of arginine in mutated cells. When SLC7A7/y+LAT1 was silenced in human THP-1 macrophages and A549 airway epithelial cells by means of short interference RNA (siRNA), a significant induction of the expression and release of the inflammatory mediators IL1ß and TNFα was observed, no matter the intracellular arginine availability. This effect was mainly regulated at transcriptional level through the activation of NFκB signaling pathway. Moreover, since respiratory epithelial cells are the important sources of chemokines in response to pro-inflammatory stimuli, the effect of IL1ß has been addressed on SLC7A7 silenced A549 cells. Results obtained indicated that the downregulation of SLC7A7/y+LAT1 markedly strengthened the stimulatory effect of the cytokine on CCL5/RANTES expression and release without affecting the levels of CXCL8/IL8. Consistently, also the conditioned medium of silenced THP-1 macrophages activated airway epithelial cells in terms of CCL5/RANTES expression due to the presence of elevated amount of proinflammatory cytokines. In conclusion, our results point to a novel thus far unknown function of SLC7A7/y+LAT1, that, under physiological conditions, besides transporting arginine, may act as a brake to restrain inflammation.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/imunologia , Cadeias Leves da Proteína-1 Reguladora de Fusão/metabolismo , Inflamação/imunologia , Macrófagos/imunologia , Aminoacidúrias Renais/imunologia , Mucosa Respiratória/imunologia , Células A549 , Erros Inatos do Metabolismo dos Aminoácidos/genética , Sistema y+L de Transporte de Aminoácidos , Quimiocina CCL5/metabolismo , Cadeias Leves da Proteína-1 Reguladora de Fusão/genética , Inativação Gênica , Humanos , Inflamação/genética , Interleucina-1beta/metabolismo , Mutação/genética , NF-kappa B/metabolismo , Fenótipo , RNA Interferente Pequeno/genética , Aminoacidúrias Renais/genética , Células THP-1 , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Abstract A 66-year-old woman showing renal dysfunction with elevated serum alkaline phosphatase and anti-SS-A antibody was admitted. A labial salivary gland biopsy showing infiltration of mononuclear cells and positive anti-SS-A antibody with sicca symptoms led to a diagnosis of primary Sjögren's syndrome (SS). Fanconi's syndrome was diagnosed by renal tubular acidosis along with renal glucosuria or aminoaciduria and multiple bone fractures on bone scintigraphy. Typical bilateral pulmonary shadows were confirmed as organizing pneumonia (OP) determined by the analysis of bronchoalveolar lavage fluid and transbronchial lung biopsy. A rare complication of Fanconi's syndrome with OP in SS is described.
