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Toll-like Receptor 3-induced Suppression via Binding of Suppressors of Cytokine Signaling 3 to Tyrosine Kinase 2

ABSTRACT: The Suppressor of cytokine signaling (SOCS) family of negative regulatory proteins are upregulated in response to several cytokines and pathogen-associated molecular patterns (PAMPs), and suppress cellular signaling responses by binding receptor phosphotyrosine residues. Exposure of bone marrow-derived dendritic cells (BMDCs) to 1D8 cells, a murine model of ovarian carcinoma, suppresses their ability to express CD40 and stimulate antigen specific responses in response to PAMPs, and in particular to poly I: C with the upregulated SOCS3 transcript and protein levels. The ectopic expression of SOCS3 in both the macrophage cell line RAW264.7 and BMDCs decreased signaling in response to both poly I:C and IFNα. Further, knockdown of SOCS3 transcripts significantly enhanced the responses of RAW264.7 and BMDCs to both poly I: C and IFNα. Immunoprecipitation and pull-down studies demonstrate that SOCS3 binds to the IFNα receptor TYK2. Since poly I: C triggers autocrine IFNα signaling, binding of SOCS3 to TYK2 may thereby suppress the activation of BMDCs by polyI:C and IFNα. Thus, elevated levels of SOCS3 in tumor-associated DCs may potentially resist the signals induced by TLR3 ligands and type I interferon to decrease DC activation via binding with IFNα receptor TyK2. Keywords: Response to intracellular signaling from tumor cells by coculture or treated medium

ORGANISM(S): Mus musculus

PROVIDER: GSE10741 | GEO | 2009/02/23

SECONDARY ACCESSION(S): PRJNA107515

REPOSITORIES: GEO

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Project description:Background: Toll-like family of receptors recognizes pathogen-associated molecular patterns (PAMPs) from different organisms. TLR4 is the receptor for bacterial lipopolysaccharide (LPS), dsRNA viral mimic poly(I:C) binds to TLR3, and bacterial CpG DNA signals through TLR9. TLR4 signaling is mediated by adaptor molecules Myd88 and TRIF while TLR3 pathway involves only the TRIF adaptor and TLR9 signals solely through Myd88. Methods: To identify genes other than those in TLR pathways that mediate macrophage response to different PAMPs, RAW264.7 cells were stimulated with LPS, poly(I:C), or CpG DNA, and RNA was profiled on microarrays 6 hrs and 24 hrs post-treatment. Gene expression data were analyzed to determine genes, pathways and transcriptional networks that are in common and unique to each of the three TLR stimuli. Potentially novel candidates revealed by this analysis were tested for their role in innate immunity using RNA interference. Results: Many genes are differentially regulated by LPS and poly(I:C) at both 6 hrs and 24 hrs following treatment, while CpG DNA elicits a much less pronounced transcriptional response. By analyzing gene expression data for networks and pathways, we prioritized differentially expressed genes that are in common to all three PAMPs as well as those shared by LPS and poly(I:C). Knockdown by RNA interference of two genes, Plec1 and TPST1, inhibited production of IL-6 in response to LPS in cultured macrophages. Conclusions: We have identified novel innate immunity genes that may be important in macrophage response to LPS, poly(I:C), and CpG DNA stimuli. Our results provide potential biomarkers and therapeutic targets that should be further investigated in mice and human populations. Keywords: time course For each treatment (Sigma LPS, LIST LPS, and media only), three biological replicates (separate macrophage cultures and RNA isolations) were profiled. Each sample was labeled with Cy3 and Cy5 and co-hybridized with Stratagene Universal Mouse Reference (dye flip techical replicates). Expression at 2 timepoints (6 and 24 hours post-treatment) was assessed.

Project description:Molecular Pathways and Transcriptional Networks Involved in the Macrophage Response to LPS, poly(I:C) and CpG DNA Stimulation Background: Toll-like family of receptors recognizes pathogen-associated molecular patterns (PAMPs) from different organisms. TLR4 is the receptor for bacterial lipopolysaccharide (LPS), dsRNA viral mimic poly(I:C) binds to TLR3, and bacterial CpG DNA signals through TLR9. TLR4 signaling is mediated by adaptor molecules Myd88 and TRIF while TLR3 pathway involves only the TRIF adaptor and TLR9 signals solely through Myd88. Methods: To identify genes other than those in TLR pathways that mediate macrophage response to different PAMPs, RAW264.7 cells were stimulated with LPS, poly(I:C), or CpG DNA, and RNA was profiled on microarrays 6 hrs and 24 hrs post-treatment. Gene expression data were analyzed to determine genes, pathways and transcriptional networks that are in common and unique to each of the three TLR stimuli. Potentially novel candidates revealed by this analysis were tested for their role in innate immunity using RNA interference. Results: Many genes are differentially regulated by LPS and poly(I:C) at both 6 hrs and 24 hrs following treatment, while CpG DNA elicits a much less pronounced transcriptional response. By analyzing gene expression data for networks and pathways, we prioritized differentially expressed genes that are in common to all three PAMPs as well as those shared by LPS and poly(I:C). Knockdown by RNA interference of two genes, Plec1 and TPST1, inhibited production of IL-6 in response to LPS in cultured macrophages. Conclusions: We have identified novel innate immunity genes that may be important in macrophage response to LPS, poly(I:C), and CpG DNA stimuli. Our results provide potential biomarkers and therapeutic targets that should be further investigated in mice and human populations. For each treatment (LPS, polyIC, CpG DNA, media only), three biological replicates (separate macrophage cultures and RNA isolations) were profiled. Each sample was labeled with Cy3 and Cy5 and co-hybridized with Stratagene Universal Mouse Reference (dye flip techical replicates). Expression at 2 timepoints (6 and 24 hours post-treatment) was assessed.

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Toll-like Receptor 3-induced Suppression via Binding of Suppressors of Cytokine Signaling 3 to Tyrosine Kinase 2

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