Genome-wide comparison between IL-17 and combined TNF-alpha/IL-17 induced genes in primary murine hepatocytes

Abstract

BackgroundCytokines such as TNF-alpha and IL-1beta are known for their contribution to inflammatory processes in liver. In contrast, the cytokine IL-17 has not yet been assigned a role in liver diseases. IL-17 can cooperate with TNF-alpha to induce a synergistic response on several target genes in different cell lines, but no data exist for primary hepatocytes. To enhance our knowledge on the impact of IL-17 alone and combined with TNF-alpha in primary murine hepatocytes a comprehensive microarray study was designed. IL-1beta was included as this cytokine is suggested to act in a similar manner as the combination of TNF-alpha and IL-17, especially with respect to its role in mRNA stabilization.ResultsThe present microarray analysis demonstrates that primary murine hepatocytes responded to IL-17 stimulation by upregulation of chemokines and genes, which are functionally responsible to increase and sustain inflammation. Cxcl2, Nfkbiz and Zc3h12a were strongly induced, whereas the majority of the genes were only very moderately up-regulated. Promoter analysis revealed involvement of NF-kappaB in the activation of many genes. Combined stimulation of TNF-alpha/IL-17 resulted in enhanced induction of gene expression, but significantly synergistic effects could be applied only to a few genes, such as Nfkbiz, Cxcl2, Zc3h12 and Steap4. Comparison of the gene expression profile obtained after stimulation of TNF-alpha/IL-17 versus IL-1beta proposed an "IL-1beta-like effect" of the latter cytokine combination. Moreover, evidence was provided that modulation of mRNA stability may be a major mechanism by which IL-17 regulates gene expression in primary hepatocytes. This assumption was exemplarily proven for Nfkbiz mRNA for the first time in hepatocytes. Our studies also suggest that RNA stability can partially be correlated to the existence of AU rich elements, but further mechanisms like the RNase activity of the up-regulated Zc3h12a have to be considered.ConclusionsOur microarray analysis gives new insights in IL-17 induced gene expression in primary hepatocytes highlighting the crosstalk with the NF-kappaB signaling pathway. Gene expression profile suggests IL-17 alone and in concert with TNF-alpha a role in sustaining liver inflammatory processes. IL-17 might exceed this function by RNA stabilization.

Transcriptome analysis of peripheral blood mononuclear cells in human subjects following a 36 h fast provides evidence of effects on genes regulating inflammation, apoptosis and energy metabolism

“…In fact, the simultaneous down-regulation of TNF, interleukin 1b (IL1B), the chemokine CXCL2, the immediate early genes IER3 and NFKBIZ is suggestive of a moderate anti-inflammatory response to the extended fast. Both TNF and IL1B are known to stimulate the expression of CXCL2, NFKBIZ and IER3 at the level of the gene transcripts in a variety of cells (Shen et al 2005;Sparna et al 2010). As reported previously, multiplex immunoassay analysis of plasma samples from the same subjects showed a small but significant reduction in circulating IL1B protein concentrations that parallels the change in PMBC IL1B mRNA levels observed here (Bouwman et al 2011).…”

The balance between IL-17 and IL-22 produced by liver-infiltrating T-helper cells critically controls NASH development in mice

“…Th22 cells have been described as a new Th subset exclusively producing IL-22, but not IL-17 or IFNγ [17,18]. Consistent with a role of adaptive immunity in hepatic inflammation, NASH was found to be associated with a Th1 cytokine response characterized by IFNγ and TNFα secretion in mice [10,19], and genome-wide analysis showed that stimulation of primary hepatocytes with IL-17 induced the expression of several inflammation-associated genes, including chemokines and C-reactive protein [20]. Finally, adaptive immunity responses may directly affect different steps of NAFLD evolution towards more severe liver diseases.…”

Interleukin-17 (IL-17) and IL-1 Activate Translation of Overlapping Sets of mRNAs, Including That of the Negative Regulator of Inflammation, MCPIP1

“…In primary hepatocytes, MCPIP1 mRNA is induced synergistically by TNF and IL-17 (10). Transcriptional induction by IL-1␤ has been demonstrated to involve the NF-B and ERK pathways and Elk-1 transcription factor (33,34).…”

“…Marked synergy in induction of gene expression has been observed with other inflammatory stimuli, e.g. TNF (9,10) or poly(I:C) (11). The IL-17 family contains several isoforms that homo-or heterodimerize and bind to members of a distinct family of IL-17 receptors.…”

“…MCPIP1 is induced upon macrophage activation with LPS (26) and in different types of cells in response to stress (30) and to IL-1 (10,31,32). In primary hepatocytes, MCPIP1 mRNA is induced synergistically by TNF and IL-17 (10).…”