RESUMO
Gastro-intestinal helminth infections trigger the release of interleukin-33 (IL-33), which induces type-2 helper T cells (Th2 cells) at the site of infection to produce IL-13, thereby contributing to host resistance in a T cell receptor (TCR)-independent manner. Here, we show that, as a prerequisite for IL-33-induced IL-13 secretion, Th2 cells required the expression of the epidermal growth factor receptor (EGFR) and of its ligand, amphiregulin, for the formation of a signaling complex between T1/ST2 (the IL-33R) and EGFR. This shared signaling complex allowed IL-33 to induce the EGFR-mediated activation of the MAP-kinase signaling pathway and consequently the expression of IL-13. Lack of EGFR expression on T cells abrogated IL-13 expression in infected tissues and impaired host resistance. EGFR expression on Th2 cells was TCR-signaling dependent, and therefore, our data reveal a mechanism by which antigen presentation controls the innate effector function of Th2 cells at the site of inflammation.
Assuntos
Receptores ErbB/imunologia , Interleucina-13/imunologia , Interleucina-33/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Células Th2/imunologia , Anfirregulina/imunologia , Anfirregulina/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Receptores ErbB/genética , Receptores ErbB/metabolismo , Expressão Gênica/genética , Expressão Gênica/imunologia , Perfilação da Expressão Gênica/métodos , Células HEK293 , Humanos , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-33/genética , Interleucina-33/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Nematospiroides dubius/imunologia , Nematospiroides dubius/fisiologia , Nocardia/imunologia , Nocardia/fisiologia , Nocardiose/imunologia , Nocardiose/metabolismo , Nocardiose/microbiologia , Receptores de Antígenos de Linfócitos T/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Infecções por Strongylida/imunologia , Infecções por Strongylida/metabolismo , Infecções por Strongylida/parasitologia , Células Th2/metabolismoRESUMO
INTRODUCTION: MicroRNA 122 (miR-122) is a new circulating biomarker for liver injury, which increases earlier than conventional markers in patients with acetaminophen hepatotoxicity. However, as co-ingestion of ethanol is common with drug overdose, a confounding effect of acute ethanol consumption on serum miR-122 must be examined. METHODS: Blood was collected from healthy volunteers before and after recreational consumption of ethanol. Routine biochemistry and haematology measurements were performed, and serum miR-122 was measured by qPCR. The primary outcome was the difference in serum miR-122 with ethanol consumption. RESULTS: We recruited 18 participants (72% male). Their mean serum ethanol concentration was 113 mg/dl (95% confidence interval [CI] 91-135 mg/dl) after consuming ethanol. Serum miR-122 increased from a mean of 71.3 million (95% CI 29.3-113.2 million) to 139.1 million (95% CI 62.6-215.7 million) copies/ml (2.2-fold increase). There was no significant difference in serum alanine aminotransferase activity before and after ethanol consumption. CONCLUSION: miR-122 increased with moderate ethanol consumption, but the fold change was modest. As increases with acetaminophen toxicity are 100- to 10 000-fold, moderate ethanol intoxication is unlikely to confound the use of this biomarker of hepatotoxicity.
