Absence of keratin 8 confers a paradoxical microflora-dependent resistance to apoptosis in the colon

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)


Interna författare/redaktörer


Publikationens författare: Habtezion A, Toivola DM, Asghar MN, Kronmal GS, Brooks JD, Butcher EC, Omary MB
Förläggare: NATL ACAD SCIENCES
Publiceringsår: 2011
Tidskrift: Proceedings of the National Academy of Sciences
Tidskriftsakronym: P NATL ACAD SCI USA
Volym: 108
Nummer: 4
Artikelns första sida, sidnummer: 1445
Artikelns sista sida, sidnummer: 1450
Antal sidor: 6
ISSN: 0027-8424


Abstrakt

Keratin 8 (K8) is a major intermediate filament protein present in enterocytes and serves an antiapoptotic function in hepatocytes. K8-null mice develop colonic hyperplasia and colitis that are reversed after antibiotic treatment. To investigate the pathways that underlie the mechanism of colonocyte hyperplasia and the normalization of the colonic phenotype in response to antibiotics, we performed genome-wide microarray analysis. Functional annotation of genes that are differentially regulated in K8(-/-) and K8(+/+) isolated colon crypts (colonocytes) identified apoptosis as a major altered pathway. Exposure of K8(-/-) colonocytes or colon organ ("organoid") cultures, but not K8(-/-) small intestine organoid cultures, to apoptotic stimuli showed, surprisingly, that they are resistant to apoptosis compared with their wild-type counterparts. This resistance is not related to inflammation per se because T-cell receptor alpha-null (TCR-alpha(-/-)) and wild-type colon cultures respond similarly upon induction of apoptosis. Following antibiotic treatment, K8(-/-) colonocytes and organ cultures become less resistant to apoptosis and respond similarly to the wild-type colonocytes. Antibiotics also normalize most differentially up-regulated genes, including survivin and beta 4-integrin. Treatment of K8(-/-) mice with anti-beta 4-integrin antibody up-regulated survivin, and induced phosphorylation of focal adhesion kinase with decreased activation of caspases. Therefore, unlike the proapoptotic effect of K8 mutation or absence in hepatocytes, lack of K8 confers resistance to colonocyte apoptosis in a microflora-dependent manner.

Senast uppdaterad 2019-17-11 vid 04:01