Regulatory Network of Inflammation Downstream Proteinase-Activated Receptors

Here, cDNA array experiments determined inflammatory genes whose expression is dependent on PAR1 activation. For this purpose, we compared the alteration in gene expression in wild type and PAR1-/- mice induced by classical pro-inflammatory stimuli (LPS, SP, and antigen). 75 transcripts were considered to be dependent on PAR-1 activation and further annotated in silico by Ingenuity Pathways Analysis and gene ontology (GO). Selected transcripts were target validated by real-time PCR. Among PAR1-dependent transcripts, the following have been implicated in the inflammatory process: b2m, ccl7, cd200, cd63, cdbpd, cfl1, dusp1, fkbp1a, fth1, hspb1, marcksl1, mmp2, myo5a, nfkbia, pax1, plaur, ppia, ptpn1, ptprcap, s100a10, sim2, and tnfaip2. However, a balanced response to signals of injury requires a transient cellular activation of a panel of genes together with inhibitory systems which temper the overwhelming inflammation. In this context, the activation of genes such as dusp1 and nfkbia seems to counter-balance the inflammatory response to PAR activation by avoiding prolonged activation of p38 MAPK and increased cytokine production. In contrast, transcripts such as arf6 and dcnt1 that are involved in the mechanism of PAR re-sensitization would tend to perpetuate the inflammatory reaction in response to common pro-inflammatory stimuli. Keywords: time course, stress response, genetic modification To determine the time course of gene-expression in urinary bladders in response to saline, SP, or LPS, challenge of wild type control and PAR1-/- mice. We analyzed two animal strains: C57bl6 (WT): GSM144550, GSM144556, GSM144557, GSM144558, GSM144559 PAR1ko: GSM144551, GSM144552, GSM144553, GSM144554, GSM144555 We used the following agents: Saline: GSM144550; GSM144551 LPS: GSM144552, GSM144553, GSM144556, GSM144557 SP: GSM144554, GSM144555; GSM144558; GSM144559 The following time points: 4 hours: GSM144552; GSM144554; GSM144556; GSM144558 24 hours: GSM144550; GSM144551; GSM144553; GSM144555; GSM144557; GSM144559 No replicate is included. No dye-swaps.