Control of the expression of inflammatory response genes

Abstract

The expression of genes involved in the inflammatory response is controlled both transcriptionally and post-transcriptionally. Primary inflammatory stimuli, such as microbial products and the cytokines interleukin-1 (IL-1) and tumour necrosis factor α (TNFα), act through receptors of either the Toll and IL-1 receptor (TIR) family or the TNF receptor family. These cause changes in gene expression by activating four major intracellular signalling pathways that are cascades of protein kinases: namely the three mitogen-activated protein kinase (MAPK) pathways, and the pathway leading to activation of the transcription factor nuclear factor ϰB (NFϰB). The pathways directly activate and induce the expression of a limited set of transcription factors which promote the transcription of inflammatory response genes. Many of the mRNAs are unstable, and are stabilized by the p38 MAPK pathway. Instability is mediated by clusters of the AUUUA motif in the 3″ untranslated regions of the mRNAs. Control of mRNA stability provides a means of increasing the amplitude of a response and allows rapid adjustment of mRNA levels. Not all mRNAs stabilized by p38 contain AUUUA clusters; for example, matrix metalloproteinase-1 and -3 mRNAs lack these clusters, but are stabilized. Inflammatory gene expression is inhibited by glucocorticoids. These suppress MAPK signalling by inducing a MAPK phosphatase. This may be a significant mechanism additional to that by which the glucocorticoid receptor interferes with transcription factors.

MyD88 Adapter-like (Mal)/TIRAP Interaction with TRAF6 Is Critical for TLR2- and TLR4-mediated NF-κB Proinflammatory Responses

“…Interestingly, Baltimore and co-workers (31) have suggested that TNF-␣ is expressed by the MyD88-independent pathway via interferon regulatory factor 3, which was time-dependent. Additionally, p38 has been shown to play a role in regulating both TNF-␣ message stability and protein expression (32,33). We have described previously that Mal interaction with TRAF6 mediates Erk1/2 and JNK activation (17), but not p38, which may explain the discrepancy that the MalE190A mutant is still able to induce TNF-␣ expression.…”

Biological risks for neurological abnormalities associated with hyperbilirubinemia

“…Primary inflammatory stimulus may act through membrane receptors such as the TNF-a receptor 1 (TNFR1), which cause the activation of four major intracellular signaling pathways that are cascades of protein kinases, namely the three distinct mitogen-activated protein kinase (MAPK) pathways, p38, Jun-NH 2 -terminal kinase 1 and 2 (JNK1/2) and extracellular signal-regulated kinase 1 and 2 (ERK1/2), and the one leading to activation of the nuclear factor kB (NF-kB). 27 Incubation of astrocytes with 50 mM UCB and 100 mM HSA resulted in a biphasic activation of TNFR1 during the 24 h observation period. 25 The early phase was detected as early as 15 min, peaking at 1 h, and the late phase occurred at 12 h. Although the early-phase activation may result from a direct interaction of UCB with the TNFR1, we speculate that the secondary activation may be attributed to the action of IL-1b and IL-6 produced during astrocyte exposure to UCB (Figure 1), which are known to upregulate TNFR1.…”

Functionally Independent AU-rich Sequence Motifs Regulate KC (CXCL1) mRNA

“…The production of these secreted mediators is stringently regulated at multiple mechanistic levels, including gene transcription, mRNA translation, and ultimately selective degradation of specific mRNAs (5)(6)(7)(8). Hence the pattern of gene expression depends critically upon appropriate engagement of each of these regulatory steps and deficiencies at any specific stage have been demonstrated to profoundly impact normal function (9,10).…”

“…Hence the pattern of gene expression depends critically upon appropriate engagement of each of these regulatory steps and deficiencies at any specific stage have been demonstrated to profoundly impact normal function (9,10). mRNA degradation is now widely recognized as an important regulatory step in controlling gene expression, and this is particularly true for short lived mRNAs such as those encoding cytokine and chemokine proteins (6,7,11,12). The instability of such mRNAs is determined by sequence motifs frequently located in the 3Ј untranslated region (3Ј-UTR) 1 of the message.…”

“…The instability of such mRNAs is determined by sequence motifs frequently located in the 3Ј untranslated region (3Ј-UTR) 1 of the message. The best studied of these sequences are known as adenine/ uridine rich elements (AREs) and have been demonstrated to confer marked instability and, in some cases, potent sensitivity for stabilization in response to extracellular stimuli (6,8,11,13). Moreover, ARE sequences have been reported to regulate translational efficiency that also exhibits potent stimulus sensitivity (14 -16).…”