RESUMEN
Cathelicidin is a pleiotropic host defense peptide secreted by epithelial and immune cells. Whether endogenous cathelicidin is protective against ulcerative colitis, however, is unclear. Here we sought to delineate the role of endogenous murine cathelicidin (mCRAMP) and the therapeutic efficacy of intrarectal administration of mCRAMP-encoding plasmid in ulcerative colitis using dextran sulfate sodium (DSS)-challenged cathelicidin-knockout (Cnlp(-/-)) mice as a model. Cnlp(-/-) mice had more severe symptoms and mucosal disruption than the wild-type mice in response to DSS challenge. The tissue levels of interleukin-1ß and tumor necrosis factor-α, myeloperoxidase activity and the number of apoptotic cells were increased in the colon of DSS-challenged Cnlp(-/-) mice. Moreover, mucus secretion and mucin gene expression were impaired in Cnlp(-/-) mice. All these abnormalities were reversed by the intrarectal administration of mCRAMP or mCRAMP-encoding plasmid. Taken together, endogenous cathelicidin may protect against ulcerative colitis through modulation of inflammation and mucus secretion.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/genética , Colitis Ulcerosa/terapia , Terapia Genética , Administración Rectal , Animales , Apoptosis , Colitis Ulcerosa/genética , Expresión Génica , Vectores Genéticos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Mucosa Intestinal/patología , Ratones , Ratones Noqueados , Mucinas/genética , Mucinas/metabolismo , Peroxidasa/genética , Peroxidasa/metabolismo , Plásmidos/administración & dosificación , Plásmidos/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , CatelicidinasRESUMEN
Cathelicidin, an antimicrobial peptide of the innate immune system, has been shown to modulate microbial growth, wound healing and inflammation. However, whether cathelicidin controls Helicobacter pylori infection in vivo remains unexplored. This study sought to elucidate the role of endogenous and exogenous mouse cathelicidin (CRAMP) in the protection against H. pylori infection and the associated gastritis in mice. Results showed that genetic ablation of CRAMP in mice significantly increased the susceptibility of H. pylori colonization and the associated gastritis as compared with the wild-type control. Furthermore, replenishment with exogenous CRAMP, delivered via a bioengineered CRAMP-secreting strain of Lactococcus lactis, reduced H. pylori density in the stomach as well as the associated inflammatory cell infiltration and cytokine production. Collectively, these findings indicate that cathelicidin protects against H. pylori infection and its associated gastritis in vivo. Our study also demonstrates the feasibility of using the transformed food-grade bacteria to deliver cathelicidin, which may have potential clinical applications in the treatment of H. pylori infection in humans.
Asunto(s)
Péptidos Catiónicos Antimicrobianos , Gastritis/tratamiento farmacológico , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Animales , Péptidos Catiónicos Antimicrobianos/administración & dosificación , Péptidos Catiónicos Antimicrobianos/genética , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/microbiología , Gastritis/complicaciones , Gastritis/microbiología , Gastritis/patología , Vectores Genéticos , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/microbiología , Helicobacter pylori/crecimiento & desarrollo , Helicobacter pylori/patogenicidad , Humanos , Inflamación/tratamiento farmacológico , Inflamación/microbiología , Inflamación/patología , Lactobacillus/genética , Ratones , CatelicidinasRESUMEN
Multidrug resistance (MDR) of cancer cells to a wide spectrum of anticancer drugs is a major obstacle to successful chemotherapy. It is usually mediated by the overexpression of one of the three major ABC transporters actively pumping cytotoxic drugs out of the cells. There has been great interest in the search for inhibitors toward these transporters with an aim to circumvent resistance. This is usually achieved by screening from natural product library and the subsequent structural modifications. This study reported the reversal of ABCG2-mediated MDR in drug-selected resistant cancer cell lines by a class of host defense antimicrobial peptides, the human cathelicidin LL37 and its fragments. The effective human cathelicidin peptides (LL17-32 and LL13-37) were found to increase the accumulation of mitoxantrone in cancer cell lines with ABCG2 overexpression, thereby circumventing resistance to mitoxantrone. At the effective concentrations of the cathelicidin peptides, cell proliferation of the parental cells without elevated ABCG2 expression was not affected. Result from drug efflux and ATPase assays suggested that both LL17-32 and LL13-37 interact with ABCG2 and inhibit its transport activity in an uncompetitive manner. The peptides were also found to downregulate ABCG2 protein expression in the resistant cells, probably through a lysosomal degradation pathway. Our data suggest that the human cathelicidin may be further developed for sensitizing resistant cancer cells to chemotherapy.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Péptidos Catiónicos Antimicrobianos/genética , Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/genética , Proteínas de Neoplasias/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/metabolismo , Péptidos Catiónicos Antimicrobianos/administración & dosificación , Péptidos Catiónicos Antimicrobianos/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mitoxantrona/farmacología , Proteínas de Neoplasias/metabolismo , Péptidos/administración & dosificación , Péptidos/metabolismo , Proteolisis/efectos de los fármacos , CatelicidinasRESUMEN
Ulceration in the gastrointestinal (GI) mucosa is a common disorder in humans. It has been shown that cigarette smoking is closely related to the increase of peptic ulcer and also plays an inhibitory role on ulcer healing. However, the underlying mechanisms by which cigarette smoke exerts these adverse effects remain largely unknown. It is perhaps partly due to the complexity of chemical compositions in the smoke and furthermore their pathological actions are largely undefined. In this review, we have highlighted the potential adverse effects of the toxic chemical components in cigarette smoke and summarized their possible mechanisms of actions on ulcer formation and healing in the GI tract. We also discuss in detail how cigarette smoke disturbs cell proliferation, influences mucus synthesis and secretion, delays blood vessel formation, and interferes the innate immune responses during ulceration and repair in the GI mucosa.