title: Acidic environment activates inflammatory programs in fibroblasts via a cAMP-MAPK pathway.
abstract: The tissue micromilieu in disorders (inflammation, ischemia, tumor) often shows pronounced metabolic acidosis that may alter signaling and transcriptional activity in resident cells which can be of special importance for omnipresent fibroblasts. In the present study we investigated the impact of metabolic acidosis on rat fibroblasts with special emphasis on their role in inflammation by regulation of TNF-α, MCP-1, COX-2 and iNOS expression and the signaling pathways involved. Extracellular acidosis led to an enhanced expression of TNF-α, COX-2 and iNOS in parallel to an activation of p38 and ERK1/2 kinases that was not observed by sole intracellular acidosis. Accordingly, the protein amounts of TNF-α and COX-2 as well as the production of nitrate and nitrite were elevated. Acidosis-induced expression of COX-2 and iNOS depended on p38 kinase, but not on ERK1/2. In contrast acidosis-induced TNF-α expression was independent of both kinases. Although GPR4, GPR68 and GPR132 are expressed in fibroblasts, the involvement of these potential candidate pH sensors could be ruled out since no acidosis-induced elevation in intracellular cAMP or free calcium content was observed. Furthermore our data show that MAPK activation by an acidic micromilieu depends on Ser/Thr phosphatase activity, but not on the production of reactive oxygen species and is sensitive to cAMP antagonism by Rp-cAMPS. In conclusion, our results show that an acidic microenvironment induces a differential transcriptional program of pathological relevant genes in fibroblasts via the cAMP-phosphatase-MAPK pathway and thereby generates a parainflammatory situation that can result in tissue remodeling.
authors.affiliation: Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, Germany. Electronic address: anne.riemann@medizin.uni-halle.de.
authors.forename: A
authors.initials: A
authors.lastname: Riemann
authors.affiliation: Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ihling
authors.affiliation: Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schneider
authors.affiliation: Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Thews
authors.affiliation: Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gekle
mesh_terms: D000138:Acidosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D000143:Acids / Q000378:metabolism*; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology*; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D042541:Intracellular Space / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000143:Acids; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Acidosis; Fibroblast; Inflammation; MAP kinase signaling