Acidosis differently modulates the inflammatory program in monocytes and macrophages.
Inflammation, ischemia or the microenvironment of solid tumors is often accompanied by a reduction of extracellular pH (acidosis) that stresses the cells and acts on cellular signaling and transcription. The effect of acidosis on the expression of various inflammatory markers, on functional parameters (migration, phagocytic activity) and on signaling pathways involved was studied in monocytic cells and macrophages. In monocytic cell lines acidosis led to a reduction in expression of most of the inflammatory mediators, namely IL-1ß, IL-6, TNF-α, MCP-1, COX-2 and osteopontin. In primary human monocytes MCP-1 and TNF-α were reduced but COX-2 and IL-6 were increased. In RAW264.7 macrophage cell line IL-1ß, COX-2 and iNOS expression was increased, whereas MCP-1 was reduced similar to the effect in monocytic cells. For primary human monocyte-derived macrophages the regulation of inflammatory markers by acidosis depended on activation state, except for the acidosis-induced downregulation of MCP-1 and TNF-α. Acidosis affected functional immune cell behavior when looking at phagocytic activity which was increased in a time-dependent manner, but cellular motility was not changed. Neither ERK1/2 nor CREB signaling was stimulated by the reduction of extracellular pH. However, p38 was activated by acidosis in RAW264.7 cells and this activation was critical for the induction of IL-1ß, COX-2 and iNOS expression. In conclusion, acidosis may impede the recruitment of immune cells, but fosters inflammation when macrophages are present by increasing the level of COX-2 and iNOS and by functionally forcing up the phagocytic activity.
Julius-Bernstein-Institute of Physiology, University Halle-Wittenberg, Germany. Electronic address: anne.riemann@medizin.uni-halle.de.
Anne
A
Riemann
Julius-Bernstein-Institute of Physiology, University Halle-Wittenberg, Germany.
Hanna
H
Wußling
Dept. of Internal Medicine III, University Halle-Wittenberg, Germany.
Harald
H
Loppnow
Dept. of Internal Medicine III, University Halle-Wittenberg, Germany.
Hang
H
Fu
Julius-Bernstein-Institute of Physiology, University Halle-Wittenberg, Germany.
Sarah
S
Reime
Julius-Bernstein-Institute of Physiology, University Halle-Wittenberg, Germany.
Oliver
O
Thews
D000138:Acidosis / Q000150:complications / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009000:Monocytes / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D010587:Phagocytosis; D000067996:RAW 264.7 Cells; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
D018932:Chemokine CCL2; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases
Acidosis; Immune cell function; Inflammation; Macrophages; Phagocytosis