Myeloid p38α signaling promotes intestinal IGF-1 production and inflammation-associated tumorigenesis.
EMBO Mol Med
; 10(7)2018 07.
Article
em En
| MEDLINE
| ID: mdl-29907597
ABSTRACT
The protein kinase p38α plays a key role in cell homeostasis, and p38α signaling in intestinal epithelial cells protects against colitis-induced tumorigenesis. However, little is known on the contribution of p38α signaling in intestinal stromal cells. Here, we show that myeloid cell-specific downregulation of p38α protects mice against inflammation-associated colon tumorigenesis. The reduced tumorigenesis correlates with impaired detection in the colon of crucial chemokines for immune cell recruitment. We identify insulin-like growth factor-1 (IGF-1) as a novel mediator of the p38α pathway in macrophages. Moreover, using genetic and pharmacological approaches, we confirm the implication of IGF-1 produced by myeloid cells in colon inflammation and tumorigenesis. We also show a correlation between IGF-1 pathway activation and the infiltration of myeloid cells with active p38α in colon samples from patients with ulcerative colitis or colon cancer. Altogether, our results uncover an important role for myeloid IGF-1 downstream of p38α in colitis-associated tumorigenesis and suggest the interest in evaluating IGF-1 therapies for inflammation-associated intestinal diseases, taking into consideration IGF-1 signaling and immune cell infiltration in patient biopsies.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Insulin-Like I
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Colite
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Neoplasias do Colo
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Células Mieloides
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Proteína Quinase 14 Ativada por Mitógeno
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Carcinogênese
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Mucosa Intestinal
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
EMBO Mol Med
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Espanha