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1.
J Innate Immun ; 1(3): 254-67, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20375583

RESUMO

LL-37, the only member of the cathelicidin family of cationic host defence peptides in humans, has been shown to mediate multiple immunomodulatory effects and as such is thought to be an important component of innate immune responses. A growing body of evidence indicates that LL-37 affects lung mucosal responses to pathogens through altered regulation of cell migration, proliferation, wound healing and cell apoptosis. These functions are consistent with LL-37 playing a role in regulating lung epithelial inflammatory responses; however, that role has not been clearly defined. In this report we have demonstrated that host defence peptide LL-37 induced cytokine (IL-6) and chemokine (CXCL-1/GRO-alpha and CXCL-8/IL-8) release from human bronchial epithelial cells. It was demonstrated that LL-37-mediated IL-6 release was time and dose dependent and that LL-37 up-regulated this pleiotropic cytokine at the transcriptional level. Using specific inhibitors it was shown that NF-kappaB signaling led to the LL-37-stimulated production of IL-6. LL-37 stimulation of airway epithelial cells activated NF-kappaB signaling, as demonstrated by the phosphorylation and degradation of Ikappa-Balpha, and consequent nuclear translocation of p65 and p50 NF-kappaB subunits. Furthermore this host defence peptide augmented flagellin-mediated cytokine production, indicating that LL-37 likely modulates Toll-like receptor 5-mediated responses.


Assuntos
Catelicidinas/imunologia , Células Epiteliais/imunologia , Interleucina-6/metabolismo , Pulmão/imunologia , NF-kappa B/metabolismo , Peptídeos Catiônicos Antimicrobianos , Catelicidinas/metabolismo , Catelicidinas/farmacologia , Linhagem Celular , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Flagelina/imunologia , Flagelina/metabolismo , Humanos , Pulmão/citologia , Pulmão/metabolismo , Transdução de Sinais
2.
Nat Biotechnol ; 25(4): 465-72, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17384586

RESUMO

We show that an innate defense-regulator peptide (IDR-1) was protective in mouse models of infection with important Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and Salmonella enterica serovar Typhimurium. When given from 48 h before to 6 h after infection, the peptide was effective by both local and systemic administration. Because protection by IDR-1 was prevented by in vivo depletion of monocytes and macrophages, but not neutrophils or B- and T-lymphocytes, we conclude that monocytes and macrophages are key effector cells. IDR-1 was not directly antimicrobial: gene and protein expression analysis in human and mouse monocytes and macrophages indicated that IDR-1, acting through mitogen-activated protein kinase and other signaling pathways, enhanced the levels of monocyte chemokines while reducing pro-inflammatory cytokine responses. To our knowledge, an innate defense regulator that counters infection by selective modulation of innate immunity without obvious toxicities has not been reported previously.


Assuntos
Anti-Infecciosos/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Peptídeos/farmacologia , Animais , Anti-Infecciosos/uso terapêutico , Anti-Infecciosos/toxicidade , Infecções Bacterianas/tratamento farmacológico , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/imunologia , Lipopolissacarídeos/farmacologia , Camundongos , Modelos Imunológicos , Peptídeos/toxicidade , Resultado do Tratamento
3.
J Leukoc Biol ; 80(6): 1563-74, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16943385

RESUMO

Genomic approaches can be exploited to expose the complexities and conservation of biological systems such as the immune network across various mammalian species. In this study, temporal transcriptional expression profiles were analyzed in human and bovine monocytic cells in response to the TLR-4 agonist, LPS, in the presence or absence of their respective host defense peptides. The cathelicidin peptides, human LL-37 and bovine myeloid antimicrobial peptide-27 (BMAP-27), are homologs, yet they have diverged notably in terms of sequence similarity. In spite of their low sequence similarities, both of these cathelicidin peptides demonstrated potent, antiendotoxin activity in monocytic cells at low, physiologically relevant concentrations. Microarray studies indicated that 10 ng/ml LPS led to the up-regulation of 125 genes in human monocytes, 106 of which were suppressed in the presence of 5 mug/ml of the human peptide LL-37. To confirm and extend these data, temporal transcriptional responses to LPS were assessed in the presence or absence of the species-specific host defense peptides by quantitative real-time PCR. The transcriptional trends of 20 LPS-induced genes were analyzed in bovine and human monocytic cells. These studies demonstrated conserved trends of gene responses in that both peptides were able to profoundly suppress many LPS-induced genes. Consistent with this, the human and bovine peptides suppressed LPS-induced translocation of NF-kappaB subunits p50 and p65 into the nucleus of monocytic cells. However, there were also distinct differences in responses to LPS and the peptides; for example, treatment with 5 mug/ml BMAP-27 alone tended to influence gene expression (RELA, TNF-alpha-induced protein 2, MAPK phosphatase 1/dual specificity phosphatase 1, IkappaBkappaB, NFkappaBIL1, TNF receptor-associated factor 2) to a greater extent than did the same amount of human LL-37. We hypothesize that the immunomodulatory effects of the species-specific host defense peptides play a critical role in regulating inflammation and represent an evolutionarily conserved mechanism for maintaining homeostasis, although the sequence divergence of these peptides is substantial.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase/imunologia , Lipopolissacarídeos/farmacologia , Monócitos/imunologia , Transcrição Gênica/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/genética , Transporte Ativo do Núcleo Celular/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/imunologia , Bovinos , Linhagem Celular , Núcleo Celular/imunologia , Núcleo Celular/metabolismo , Relação Dose-Resposta a Droga , Evolução Molecular , Regulação da Expressão Gênica/imunologia , Genoma Humano/imunologia , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Lipopolissacarídeos/imunologia , Monócitos/metabolismo , Transcrição Gênica/imunologia , Catelicidinas
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