Subcompartments of the macrophage recycling endosome direct the differential secretion of IL-6 and TNFalpha.
Activated macrophages secrete an array of proinflammatory cytokines, including tumor necrosis factor-alpha (TNFalpha) and interleukin 6 (IL-6), that are temporally secreted for sequential roles in inflammation. We have previously characterized aspects of the intracellular trafficking of membrane-bound TNFalpha and its delivery to the cell surface at the site of phagocytic cups for secretion (Murray, R.Z., J.G. Kay, D.G. Sangermani, and J.L. Stow. 2005. Science. 310:1492-1495). The trafficking pathway and surface delivery of IL-6, a soluble cytokine, were studied here using approaches such as live cell imaging of fluorescently tagged IL-6 and immunoelectron microscopy. Newly synthesized IL-6 accumulates in the Golgi complex and exits in tubulovesicular carriers either as the sole labeled cargo or together with TNFalpha, utilizing specific soluble NSF attachment protein receptor (SNARE) proteins to fuse with the recycling endosome. Within recycling endosomes, we demonstrate the compartmentalization of cargo proteins, wherein IL-6 is dynamically segregated from TNFalpha and from surface recycling transferrin. Thereafter, these cytokines are independently secreted, with TNFalpha delivered to phagocytic cups but not IL-6. Therefore, the recycling endosome has a central role in orchestrating the differential secretion of cytokines during inflammation.
Manderson
Anthony P
AP
Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia.
Kay
Jason G
JG
Hammond
Luke A
LA
Brown
Darren L
DL
Stow
Jennifer L
JL
D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D018274:Electroporation; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D019084:Fluorescent Antibody Technique, Indirect; D005456:Fluorescent Dyes / Q000378:metabolism; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008856:Microscopy, Fluorescence; D034741:RNA, Small Interfering / Q000494:pharmacology; D012235:Rhodamines / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism* / Q000648:ultrastructure
D018076:DNA, Complementary; D005456:Fluorescent Dyes; D015850:Interleukin-6; D034741:RNA, Small Interfering; D012235:Rhodamines; D014409:Tumor Necrosis Factor-alpha; C067297:8-aminohexylamino cAMP; C005358:tetramethylrhodamine; D000242:Cyclic AMP