RESUMO
Recent evidence has revealed an unsuspected suppressive role played by neutrophils during microbial infections. An especially intriguing aspect of this role is the ability of neutrophils to produce interleukin (IL)-10 following interaction with lipopolysaccharide (LPS)-stimulated regulatory T (Treg) cells. The present study demonstrates that generation of IL-10 in neutrophils induced by LPS-stimulated Treg cells required direct cell-cell contact. This effect was dependent on the binding of CD11b and intercellular adhesion molecule 1. Neither stimulation of neutrophils with LPS nor their culture with unstimulated Treg cells, CD3/CD28 monoclonal antibodies-stimulated Treg cells, or T conventional cells affected intracellular IL-10 expression. IL-10-positive neutrophils were also induced by exogenous IL-10, providing an example of a positive feedback loop. Both LPS-stimulated Treg cells and exogenous IL-10 exclusively promoted posttranslational modifications of histones, H3K4me3 and H3Ac Lys4, that activate IL-10 genomic locus in neutrophils, while the promoter of IL-10 gene was inactive in resting, LPS-stimulated neutrophils, following blocking of direct interaction with LPS-stimulated Treg cells or in LPS-preactivated neutrophils incubated with LPS-stimulated Treg cells. We additionally confirmed the presence of IL-10-producing neutrophils in vivo in patients with periodontal abscess induced by Gram-negative bacteria, as opposed to neutrophils isolated from the site of aseptic inflammation in patients with neuromyelitis optica.
Assuntos
Comunicação Celular/imunologia , Interleucina-10/imunologia , Neutrófilos/imunologia , Processamento de Proteína Pós-Traducional , Linfócitos T Reguladores/imunologia , Anticorpos Monoclonais/farmacologia , Sítios de Ligação , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Antígenos CD28/genética , Antígenos CD28/imunologia , Complexo CD3/genética , Complexo CD3/imunologia , Técnicas de Cocultura , Retroalimentação Fisiológica , Histonas/genética , Histonas/imunologia , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/imunologia , Interleucina-10/genética , Interleucina-10/farmacologia , Lipopolissacarídeos/farmacologia , Ativação Linfocitária , Neuromielite Óptica/genética , Neuromielite Óptica/imunologia , Neuromielite Óptica/patologia , Neutrófilos/patologia , Abscesso Periodontal/genética , Abscesso Periodontal/imunologia , Abscesso Periodontal/patologia , Cultura Primária de Células , Regiões Promotoras Genéticas , Ligação Proteica , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologiaRESUMO
Mutations including nonsense mutations, missense mutations, splicing-site mutations, insertions, and deletions in phosphate regulating genes on the X-chromosome (PHEX) are known to be responsible for X-linked hypophosphatemic rickets. The PHEX gene encodes an endopeptidase that is involved in phosphate regulation. Herein we present a female patient with sporadic hypophosphatemic rickets harboring a novel deletion mutation (c.1586_1586+1delAG; p.Glu529GlyfsX41) at exon 14 and intron 14 junction, which caused a premature termination at codon 569 and possibly produced a truncated PHEX protein. The laboratory and radiologic findings of the patient are reviewed to correlate the impact of the two-base deletion mutations at the exon-intron junction.