Gadd45a and Gadd45b modulate innate immune functions of granulocytes and macrophages by differential regulation of p38 and JNK signaling.
Gadd45 proteins function as stress sensors in response to various physiological and environmental stressors, interacting with other cellular proteins implicated in cellular stress responses, including p38 and JNK. This study shows that mice lacking either Gadd45a or Gadd45b are defective in the recruitment of granulocytes and macrophages to the intra-peritoneal cavity following intra-peritoneal administration of the bacterial cell wall pathogen-associated molecular pattern lipopolysaccharide (LPS). Bone marrow derived granulocytes and macrophages lacking either Gadd45a or Gadd45b are shown to be impaired in their chemotactic response to LPS, as well as other inflammatory stimuli such as N-formyl-methionine-leucine-phenylalanine and IL-8. Evidence was obtained also implicating Gadd45a and Gadd45b in other myeloid innate immune functions, including reactive oxygen species production, phagocytosis, and adhesion. Gadd45a and Gadd45b activation of p38 kinase was implicated in the response of granulocytes to LPS mediated chemotaxis, whereas Gadd45a and Gadd45b curtailment of JNK activation was linked to chemotaxis of macrophages in response to LPS. Collectively, these data highlight a novel role for both Gadd45a and Gadd45b in myeloid innate immune functions by differential modulation of p38 and JNK signaling in granulocytes compared to macrophages.
Fels Institute for Cancer Research and Molecular Biology, Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Dominic M
DM
Salerno
Jennifer S
JS
Tront
Barbara
B
Hoffman
Dan A
DA
Liebermann
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002633:Chemotaxis; D006098:Granulocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D016209:Interleukin-8; D008070:Lipopolysaccharides; D048670:MAP Kinase Kinase 4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009687:Nuclear Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C490125:Gadd45b protein, mouse