Differential Expression of the Activator Protein 1 Transcription Factor Regulates Interleukin-1ß Induction of Interleukin 6 in the Developing Enterocyte

Abstract

The innate immune response is characterized by activation of transcription factors, nuclear factor kappa B and activator protein-1 and their downstream targets, the pro-inflammatory cytokines including interleukin 1β and interleukin 6. Normal development of this response in the intestine is critical to survival of the human neonate and delays can cause the onset of devastating inflammatory diseases such as necrotizing enterocolitis. Previous studies have addressed the role of nuclear factor kappa B in the development of the innate immune response in the enterocyte, however despite its central role in the control of multiple pro-inflammatory cytokine genes, little is known on the role of Activator Protein 1 in this response in the enterocyte. Here we show that the canonical Activator Protein 1 members, cJun and cFos and their upstream kinases JNK and p38 play an essential role in the regulation of interleukin 6 in the immature enterocyte. Our data supports a model whereby the cFos/cJun heterodimer and the more potent cJun homodimer downstream of JNK are replaced by less efficient JunD containing dimers, contributing to the decreased responsiveness to interleukin 1β and decreased interleukin 6 secretion observed in the mature enterocyte. The tissue specific expression of JunB in colonocytes and colon derived tissues together with its ability to repress Interleukin-1β induction of an Interleukin-6 gene reporter in the NCM-460 colonocyte suggests that induction of JunB containing dimers may offer an attractive therapeutic strategy for the control of IL-6 secretion during inflammatory episodes in this area of the intestine

Significance of dynamic evolution of TNF-α, IL-6 and intestinal fatty acid-binding protein levels in neonatal necrotizing enterocolitis

“…TNF-α is an important nuclear transcriptional regulation factor in the body, which is transduced into the nucleus under the induction of a variety of stressors, such as infection and diarrhea, mediates multiple signaling transduction pathways, such as NF-κB, PI3K, Fas/FasL and MAPK, regulates a variety of genes, such as ILs, γ-IFN and VEGF, and participates in inflammatory response, oxidative stress, immune response, embryonic development, cell proliferation, differentiation and apoptosis ( 9 , 10 ). IL-6 is an important pro-inflammatory mediator of the body and a pro-inflammatory factor of many other inflammatory cells and inflammatory media, which is one of the key factors leading to the inflammatory cascade and balance disorder ( 11 , 12 ).…”

Anti-inflammatory effects ofBifidobacterium longum subsp infantissecretions on fetal human enterocytes are mediated by TLR-4 receptors

“…We have previously reported that AP-1 is a specific nuclear transcriptional factor for IL-1␤-induced IL-6 secretion but only in immature enterocytes (9). AP-1 is composed of c-Jun and c-Fos which are phosphorylated in their active form.…”

Human Fetal-Derived Enterospheres Provide Insights on Intestinal Development and a Novel Model to Study Necrotizing Enterocolitis (NEC)

“… 15 Similarly, other signaling factors connecting TLR4 to nuclear factor-κB (NF-κB) and activator protein transcription factor–mediated inflammation were found to be up-regulated as well, whereas genes that inhibited these signaling pathways were down-regulated. 11 , 16 Together this evidence suggests that an exaggerated innate immune response to colonizing commensal bacteria mediated by TLR activation is mounted by immature intestinal epithelial cells, which could contribute to the pathogenesis of NEC.…”