Inhibition of IL-1β transcription by peptides derived from the hCMV IE2 transactivator

Abstract

The immediate early (IE) proteins of human cytomegalovirus (hCMV) have diverse roles in directing viral and host cell transcription. Among these is the ability of IE2 to induce transcription of the IL1B gene that codes for IL-1β in monocytes. This function is partially explained by interaction between IE2 and the host cell transcription factor Spi-1/PU.1 (Spi-1). We now show that maximal IE2 function also depends on productive interactions localizing to two C/EBP sites on the IL1B promoter suggesting either bi-or tri-molecular interactions between IE2, Spi-1 and C/EBPβ at two different locations on the promoter. The IE2 interaction region on Spi-1 was previously mapped to the DNAbinding ETS domain and overlaps the region of Spi-1 that interacts with the transcription factor C/ EBPβ, a factor known to be critical for the induction of IL1B in response to Toll/IL-1 receptor (TIR) family signal transduction. The Spi-1 interacting region of IE2 maps to amino acids 315-328, a sequence that also interacts with the bZIP domain of C/EBPβ. An expression vector coding for amino acids 291-364 of IE2 can suppress LPS induction of a cotransfected IL1B enhancer-promoter fragment in a monocyte cell line. This inhibition is likely the result of competition between Spi-1 and C/EBPβ, thus blunting gene induction.

Human Cytomegalovirus Immediate Early 86-kDa Protein Blocks Transcription and Induces Degradation of the Immature Interleukin-1β Protein during Virion-Mediated Activation of the AIM2 Inflammasome

“…7D). This result is consistent with previous work showing that IE86 both impairs transactivation of the pro-IL-1β promoter (48) and blocks NF-κB-dependent transcription through disruption of the binding of the protein complex to promoter DNA (49). We circumvented the natural cellular processes involved in the gene’s transcription by using an artificial constitutive promoter.…”

“…Furthermore, in vivo murine CMV models showed virus reactivation following direct administration of IL-1β (46). Interestingly, HCMV has evolved mechanisms to impair IL-1β-dependent signaling (47, 48), as well as NF-κB-dependent transcription (49), suggesting the existence of selective pressure, perhaps derived from antiviral effects of these innate processes. Surprisingly, whether the virus exhibits phenotypes that directly impair the synthesis, processing, or release of IL-1β or the caspase-1 inflammasome has been underexplored.…”

First Insights Into the Molecular Basis Association Between Promoter Polymorphisms of the Il1b Gene and Helicobacter Pylori Infection in the Sudanese Population: Computational Approach

“…(24)(25)(26) LPS-inducible IL1β expression is regulated by two regions, a proximal promoter that contains a TATA box and an upstream LPS-responsive enhancer (located between -3757 and -2729), which also known as the upstream inducible sequence. (27,28) In monocyte, this promoter is packaged into a highly accessible chromatin structure which is characterized by the constitutive association of PU.1 and C/ EBPβ, but inducible association of RNA polymerase II. (24,29,30) The following multiple transcription factors, that constitutively and inducible associate with IL-1β regulatory regions have been identi ed: Spi-1/PU.1 (Spi1), NF-κB, C/EBPβ, AP-1, TBP, SSRP, or c-Jun and c-fos.…”

First insights into the molecular basis association between promoter polymorphisms of the IL1B gene and Helicobacter pylori infection in the Sudanese population: computational approach

“…B cells, T cells, NK cells, dendritic cells, broblasts and epithelial cells, express this protein in response to a broad range of stimuli and under in ammatory conditions but in much low level (24)(25)(26). LPS-inducible IL1β expression is regulated by two regions, a proximal promoter that contains a TATA box and an upstream LPS-responsive enhancer (located between -3757 and -2729), which also known as the upstream inducible sequence (27,28). In monocyte, this promoter is packaged into a highly accessible chromatin structure which is characterized by the constitutive association of PU.1 and C/ EBPβ, but inducible association of RNA polymerase II (24,29,30).…”