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

Abstract

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...

An Immunological Perspective on Neonatal Sepsis

“…In preterm neonates, distinct microbial colonization of the gut linked to increased levels of CoNS and decreased colonization by protective commensals such as Bacteroides, Bifidobacterium, and Lactobacillus has also been associated to increased risks of neonatal sepsis [63,64] and NEC [65,66]. Data suggest that abnormal PRR signaling at mucosal surfaces in preterm infants may limit microbial diversity, thereby favoring the colonization of pathogenic micro-organisms [62,64,67]. These findings have direct clinical relevance.…”

Subclinical mastitis occurs frequently in association with dramatic changes in inflammatory/anti-inflammatory breast milk components

“…In an animal model colostral whey reduced the IL-8 inflammatory response of fetal human xenografts after an inflammatory stimulus with IL-1β and the luminal expression of TLR-4, which is an important cell receptor of the innate inflammatory response [29]. In vitro EPO and IL-10 used at concentrations found in breast milk are able to negatively control the IL-8 secretion by a fetal human enterocyte cell line.…”

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

“…When exposed to commensal organisms, activation of the innate immune response is self-limited. However, a stronger, IL-8-driven proinflammatory response is provoked in immature intestinal cells when exposed to commensal organisms (14). Microarray analysis shows that expression of genes involved in up-regulation of inflammation is increased while expression of negative regulators of inflammation is decreased in the immature intestine (Walker, unpublished data).…”