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Published online July 2, 2007
doi:10.1083/jcb.200612131
The Journal of Cell Biology, Vol. 178, No. 1, 57-69
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Manderson et al.
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Article

Subcompartments of the macrophage recycling endosome direct the differential secretion of IL-6 and TNF{alpha}



Anthony P. Manderson, Jason G. Kay, Luke A. Hammond, Darren L. Brown, and Jennifer L. Stow

Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD 4072, Australia

Correspondence to Jennifer L. Stow: j.stow{at}imb.uq.edu.au

Activated macrophages secrete an array of proinflammatory cytokines, including tumor necrosis factor-{alpha} (TNF{alpha}) 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 TNF{alpha} 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 TNF{alpha}, 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 TNF{alpha} and from surface recycling transferrin. Thereafter, these cytokines are independently secreted, with TNF{alpha} 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.

Abbreviations used in this paper: IL-6, interleukin 6; LPS, lipopolysaccharide; M6PR, mannose-6-phosphate receptor; Stx, syntaxin; Tfn, transferrin; TfnR, Tfn receptor; VAMP3, vesicle-associated membrane protein 3.


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