Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression in LPS stimulated IkappaB-beta knockout bone marrow derived macrophage (BMDM)

ABSTRACT: Inflammation is beneficial when it is part of the innate immune response, but harmful when it occurs in an unregulated, chronic manner. We now report that IkappaB-beta, a member of the classical IkappaB family, serves a dual role of both inhibiting and facilitating the inflammatory response. IkappaB-beta degradation releases NF-kappaB dimers which upregulate proinflammatory target genes such as TNF-alpha. Suprisingly absence of IkappaB-beta results in a dramatic reduction of TNF-alpha in response to LPS even though the activation of NF-kappaB is normal. The inhibition of TNF-alpha mRNA expression can be correlated to the absence of nuclear, hypophosphorylated-IkappaB-beta bound to p65:cRel heterodimers at a specific kappaB site on the TNF-alpha promoter. Therefore IkappaB-beta acts through p65:cRel dimers to maintain prolonged expression of TNF-alpha. As a result, IkappaB-beta knockout mice are resistant to LPS induced septic shock and collagen-induced arthritis, and therefore blocking IkappaB-beta might be a promising new strategy for selectively inhibiting the chronic phase of TNF-alpha producting during the inflammatory response. Wild type and IkappaB-beta knockout BMDM cells were stimulated with LPS(1ug/ml) for 0, 1, and 5 hours. RNA isolated from the cells was analyzed on Affymetrix Mouse Genome 430A 2.0 gene expression chip.

ORGANISM(S): Mus musculus

SUBMITTER: Ping Rao

PROVIDER: E-GEOD-22223 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas. It is characterized by the presence of rare Hodgkin and Reed/Sternberg (HRS) cells embedded in an extensive inflammatory infiltrate. Constitutive activation of nuclear factor-kappaB (NF-kappaB) in HRS cells which transcriptionally regulates expression of multiple anti-apoptotic factors and pro-inflammatory cytokines plays a central role in the pathogenesis of cHL (1, 2). In non-stimulated condition, NF-kappaB proteins are rendered inactive by binding to their inhibitors (IkappaB s), which sequester them in the cytoplasm. Stimulation of multiple receptors activates the IkappaB kinase (IKK) complex that phosphorylates IkappaB at two specific serine residues, followed by its ubiquitination and proteasomal degradation, thereby releasing NF-kappaB proteins and allowing their nuclear translocation (3). Recently, two studies provided further insights into the molecular mechanisms of IKK activation upon TNF stimulation (4, 5). Activation of the IKK complex and subsequent NF-kappaB activation requires Lys63 polyubiquitination of RIP1, a kinase which is recruited to the receptor upon TNF stimulation. IKK-ï§ï (NEMO), the regulatory subunit of the IKK complex, specifically recognizes these Lys63-linked polyubiquitins attached to RIP1 and thereby activates IKK and NF-kappaB (4, 5). A20 is an ubiquitin-modifying enzyme that inhibits NF-kappaB activation in succession of tumor necrosis factor (TNF) receptor and Toll-like receptor induced signals (6-8). This enzyme removes Lys63 linked ubiquitin chains from RIP1 and adds Lys48 polyubiquitins to RIP1, thereby targeting this factor for proteasomal degradation, thus explaining the molecular mechanism of NF-kappaB inhibition by A20 (6). A20 likely inhibits NF-kappaB acitivity also by additional means, including interaction with TRAF1 and TRAF2 (9). SNP 6.0 array (Affymetrix) analyses were performed according to the manufacturer's directions on DNA extracted from three Hodgkin cell lines (L1236, HDLM-2, U-HO1), HapMap samples included in the Genotyping Console Software 3.0 were used as references.

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Gene expression in LPS stimulated IkappaB-beta knockout bone marrow derived macrophage (BMDM)

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