Modulation of Human Intestinal Epithelial Cell IL-8 Secretion by Human Milk Factors

Claud, Erika C.; Savidge, Tor; Walker, W. Allan

doi:10.1203/01.pdr.0000050141.73528.ad

Cited by 133 publications

(109 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…One explanation offered is that ELGANs produce higher levels of inflammatory cytokines in response to infection than infants born at term. Looking specifically at the intestine, these data are consistent with previous findings from our laboratory demonstrating significantly higher IL-8 secretion by immature enterocytes in response to inflammatory stimuli compared with mature enterocytes (8,10). It is an intriguing possibility that proinflammatory mediators produced by the immature intestine may contribute to the pathogenesis of prematurity-associated inflammatory conditions at other sites.…”

Section: Discussionsupporting

confidence: 91%

“…The exaggerated inflammatory responses that are characteristic of the gut at this stage of development could then lead to increased tissue injury. Using models of immature and mature IEC, we have previously shown that immature enterocytes have greater IL-8 secretion in response to the endogenous inflammatory mediators IL-1␤ and tumor necrosis factor ␣ than do mature enterocytes (8,10). As a next step, we hypothesized that the immature IEC would also have a more pronounced inflammatory response to exogenous mediators, specifically bacteria.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Developmentally regulated IκB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation

Claud

Lü

Anton

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

202

145

View full text Add to dashboard Cite

Necrotizing enterocolitis is a devastating inflammatory condition of the intestine that occurs almost exclusively in premature newborns. Although its exact pathogenesis is unclear, we have postulated that it may result from a predisposition of the immature intestine to mount an unusually robust and damaging response to microbial infection. In support of this idea, we report that the IL-8 response of an immature human enterocyte cell line to bacterial infection was significantly higher than that of a mature enterocyte cell line. The response in both cell lines was flagellin-dependent. Corresponding to the difference in IL-8 production, the immature enterocytes expressed appreciably lower levels of specific IB genes when compared with the mature enterocytes. Similar developmentally regulated differences in cytokine response and IB expression were also seen in primary rat enterocytes, indicating that these observations were not peculiarities of the cell lines. Furthermore, when the level of IB␣ expression was increased in the immature cell line by transfection, the flagellin-dependent IL-8 response was attenuated. Thus, we have demonstrated a previously undescribed developmental regulation of IB expression in the intestine involved in modulating the IL-8 response to bacterial infection, which may contribute to the pathogenesis of age-specific inflammatory bowel diseases such as necrotizing enterocolitis. E nterocytes are active participants in host defense against microbial invasion. Certain aspects of this function are developmentally regulated, resulting in distinct differences between the immature and mature intestine with respect to interactions with microorganisms (1-4). Immaturity of epithelial barrier function, relative deficiencies in the expression of antimicrobial factors, and developmental variations in the pattern of epithelial surface glycosylation all contribute to the susceptibility of early postnatal intestine to bacterial infection (5-7). Concurrently, the secretion of proinflammatory cytokines is greater at earlier stages of development than in the adult. Specifically, IL-8 production in response to IL-1␤ and tumor necrosis factor ␣ has been shown to be significantly increased in the human fetal intestinal epithelial cell (IEC) line H4 and fetal intestinal organ cultures compared with the adult IEC line Caco2 and biopsies from older children (8). The combination of weaker antimicrobial defense mechanisms and exaggerated cytokine responses may render the immature gut prone to extensive inflammatory damage after infection. These properties could thus contribute to the pathogenesis of age-specific diseases such as necrotizing enterocolitis (NEC), an ischemic and inflammatory bowel necrosis that primarily affects premature neonates after the initiation of enteral feeding.We have postulated a model of NEC pathogenesis in which early feeding results in exposure to numbers and types of bacteria that the premature intestine is ill-equipped to handle (9). The exaggerated inflammatory responses that are cha...

show abstract

Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Developmentally regulated IκB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation

Claud

Lü

Anton

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

202

145

View full text Add to dashboard Cite

show abstract

“…This treatment resulted in increased villus height, increased proliferation, decreased apoptosis, and an increase in GLP-2 plasma levels. The intestinotrophic effect of butyrate may be mediated through GLP-2 (9). Enteral feeding appears to stimulate the development of the barrier function of the infant intestine.…”

Section: Session Ii: Mechanisms Of Diseasementioning

confidence: 99%

“…NEC is marked by immature 511 expression and regulation of nuclear factor kappa B (NFB) (Nanthakumar and Walker, unpublished data). The inability to distinguish and respond appropriately to commensal and pathogenic microorganisms (9) and the aberrant regulation of other effector molecules such as platelet activating factor (PAF) (12) lead to a proinflammatory environment that could contribute to the pathology seen in NEC. Host defense depends on maintaining an appropriate balance between proinflammatory processes and apoptosis.…”

Section: Session Ii: Mechanisms Of Diseasementioning

confidence: 99%

New Therapies and Preventive Approaches for Necrotizing Enterocolitis: Report of a Research Planning Workshop

et al. 2007

Self Cite

View full text Add to dashboard Cite

“…Maternal TGFb1, the major anti-inflammatory cytokine in human milk provided by breast-feeding to the infant, is known to protect against gut inflammation 22 and infant wheezing. 23 Long-term exclusive breast feeding was shown to attenuate disease severity in CF, 24 and consequently, the impact of maternal TGFb1 in CF may be more prominent in patients with late diagnosis and/or delayed onset of therapeutic intervention.…”

mentioning

confidence: 99%

Transmission ratio distortion and maternal effects confound the analysis of modulators of cystic fibrosis disease severity on 19q13

et al. 2007

View full text Add to dashboard Cite

Two entities localised within in a 5 Mb interval on 19q13, that is the transforming growth factor b 1 (TGFb1) and the cystic fibrosis modifier 1, have been reported to modulate disease severity of cystic fibrosis (CF), albeit the designation of the risk allele for TGFb1 differs between studies. We have analysed genotyping data at seven microsatellite loci and four single nucleotide polymorphisms targeting the 19q13 area from 37 nuclear CF families with two affected offspring exhibiting extreme clinical phenotypes for indicators of transmission-ration distortion, maternal genetic or maternal non-genetic effects. Evidence for a transmission-ratio distortion was obtained at D19S112 (P ¼ 0.0304) near the recently characterised myotonic dystrophy locus myotonic dystrophy protein kinase (DMPK). Maternal and paternal genotype distributions were significantly different at rs1982073 (Leu10Pro at TGFb1) whereby all CF sibs heterozygous at rs1982073 inherited the Leu10 allele from their mother (P ¼ 0.000132) in our sibling panel. To ask whether the improved survival in CF over the last decades has any influence on TGFb1 allele frequencies, we analysed unrelated F508del homozygotes who were stratified by birth cohort. Sensitivity with respect to the survivor bias was reflected by significantly higher incidence of mild cystic fibrosis transmembrane conductance regulator mutation genotypes in the early born patient cohort (P ¼ 0.0169), and an allelic imbalance was also observed at TGFb1 (P ¼ 0.0664). In conclusion, the role of TGFb1 as a CF modulator, suggested from studies with a case-control setting, needs to be interpreted with caution unless family-based analysis is carried out to identify parental genetic and non-genetic effects.

show abstract

Modulation of Human Intestinal Epithelial Cell IL-8 Secretion by Human Milk Factors

Cited by 133 publications

References 63 publications

Developmentally regulated IκB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation

Developmentally regulated IκB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation

New Therapies and Preventive Approaches for Necrotizing Enterocolitis: Report of a Research Planning Workshop

Transmission ratio distortion and maternal effects confound the analysis of modulators of cystic fibrosis disease severity on 19q13

Contact Info

Product

Resources

About