Down-regulation of proinflammatory capacity during apoptosis in human polymorphonuclear leukocytes.
Polymorphonuclear leukocytes (PMNs) are essential to innate immunity in humans and contribute significantly to inflammation. Although progress has been made, the molecular basis for termination of inflammation in humans is incompletely characterized. We used human oligonucleotide microarrays to identify genes encoding inflammatory mediators that were differentially regulated during the induction of apoptosis. One hundred thirty-three of 212 differentially expressed genes encoding proinflammatory factors, signal transduction mediators, adhesion molecules, and other proteins that facilitate the inflammatory response were down-regulated during the induction of apoptosis following PMN phagocytosis. Among these, 42 genes encoded proteins critical to the inflammatory response, including receptors for IL-8 beta, IL-10 alpha, IL-13 alpha 1, IL-15 alpha, IL-17, IL-18, C1q, low-density lipoprotein, IgG Fc (CD32), and formyl peptide, Toll-like receptor 6, platelet/endothelial cell adhesion molecule-1 (CD31), P-selectin (CD62), IL-1 alpha, IL-16, and granulocyte chemoattractant protein-2 were down-regulated. Many of these genes were similarly down-regulated during Fas-mediated or camptothecin-induced apoptosis. We used flow cytometry to confirm that IL-8R beta (CXCR2) and IL-1 alpha were significantly down-regulated during PMN apoptosis. We also discovered that 23 genes encoding phosphoinositide and calcium-mediated signal transduction components, which comprise complex pathways essential to the inflammatory response of host cells, were differentially regulated during PMN apoptosis. Importantly, our data demonstrate that PMNs down-regulate proinflammatory capacity at the level of gene expression during induction of apoptosis. These findings provide new insight into the molecular events that resolve inflammation following PMN activation in humans.
Kobayashi
Scott D
SD
Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
Voyich
Jovanka M
JM
Braughton
Kevin R
KR
DeLeo
Frank R
FR
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000276:immunology*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000502:physiology; D002166:Camptothecin / Q000494:pharmacology; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007155:Immunologic Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010587:Phagocytosis / Q000502:physiology; D010716:Phosphatidylinositols / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000502:physiology
D003598:Cytoskeletal Proteins; D007155:Immunologic Factors; D018836:Inflammation Mediators; D010716:Phosphatidylinositols; D019014:fas Receptor; D002118:Calcium; D002166:Camptothecin