NF-κB-Dependent Role for Cold-Inducible RNA Binding Protein in Regulating Interleukin 1β

Abstract

The cold inducible RNA binding protein (CIRBP) responds to a wide array of cellular stresses, including short wavelength ultraviolet light (UVC), at the transcriptional and post-translational level. CIRBP can bind the 3'untranslated region of specific transcripts to stabilize them and facilitate their transport to ribosomes for translation. Here we used RNA interference and oligonucleotide microarrays to identify potential downstream targets of CIRBP induced in response to UVC. Twenty eight transcripts were statistically increased in response to UVC and these exhibited a typical UVC response. Only 5 of the 28 UVC-induced transcripts exhibited a CIRBP-dependent pattern of expression. Surprisingly, 3 of the 5 transcripts (IL1B, IL8 and TNFAIP6) encoded proteins important in inflammation with IL-1β apparently contributing to IL8 and TNFAIP6 expression in an autocrine fashion. UVC-induced IL1B expression could be inhibited by pharmacological inhibition of NFκB suggesting that CIRBP was affecting NF-κB signaling as opposed to IL1B mRNA stability directly. Bacterial lipopolysaccharide (LPS) was used as an activator of NF-κB to further study the potential link between CIRBP and NFκB. Transfection of siRNAs against CIRBP reduced the extent of the LPS-induced phosphorylation of IκBα, NF-κB DNA binding activity and IL-1β expression. The present work firmly establishes a novel link between CIRBP and NF-κB signaling in response to agents with diverse modes of action. These results have potential implications for disease states associated with inflammation.

Stress Response Protein Cirp Links Inflammation and Tumorigenesis in Colitis-Associated Cancer

“…4 and 5). A recent study reported the involvement of Cirp in regulating expression of IL1b, another NF-kB target gene, in cultured fibroblasts (44). In bone marrow-derived macrophages, IL1b mRNA level was decreased in the absence of Cirp (data not shown).…”

Post-Transcriptional Regulation of DNA Damage-Responsive Gene Expression

“…UV light led to increased expression of five transcripts in a CIRBP-dependent manner. The three largest responders encoded inflammatory cytokines (15). The induction of these cytokines did not depend on a direct interaction of CIRBP with the 3¢UTRs of these mRNAs.…”

“…Therefore, transcriptional changes can give rise to secondary alterations in gene expression. For example, cold inducible RNA binding protein (CIRBP) is post-transcriptionally modified, and its expression can be increased in response to many cellular stresses, including UV light (15,164). This protein can protect specific mRNAs from degradation (ATR and CLOCK, for example), shuttle them to the cytoplasm, and stimulate translation of the encoded proteins (116,166).…”

“…This protein can protect specific mRNAs from degradation (ATR and CLOCK, for example), shuttle them to the cytoplasm, and stimulate translation of the encoded proteins (116,166). An oligonucleotide microarray strategy was used to monitor global changes in UV-induced mRNA expression in the presence and absence of small inhibitory RNAs directed against CIRBP (15). UV light led to increased expression of five transcripts in a CIRBP-dependent manner.…”

“…The induction of these cytokines did not depend on a direct interaction of CIRBP with the 3¢UTRs of these mRNAs. Instead, NFjB activity was reduced in the absence of CIRBP, so decreased cytokine expression resulted from CIRBP-dependent effects on NFjB-dependent transcription (15). Taken together, UV-induced gene expression can be achieved directly and indirectly through a variety of mechanisms that include both transcriptional and post-transcriptional mechanisms of gene regulation.…”