The response of human epithelial cells to TNF involves an inducible autocrine cascade.
Tumor necrosis factor (TNF) is a proinflammatory cytokine that induces conflicting pro- and antiapoptotic signals whose relative strengths determine the extent of cell death. TNF receptor (TNFR) has been studied in considerable detail, but it is not known how crosstalk among antagonistic pro- and antiapoptotic signals is achieved. Here we report an experimental and computational analysis of crosstalk between prodeath TNF and prosurvival growth factors in human epithelial cells. By applying classifier-based regression to a cytokine-signaling compendium of approximately 8000 intracellular protein measurements, we demonstrate that cells respond to TNF both directly, via activated TNF receptor, and indirectly, via the sequential release of transforming growth factor-alpha (TGF-alpha), interleukin-1alpha (IL-1alpha), and IL-1 receptor antagonist (IL-1ra). We refer to the contingent and time-varying series of extracellular signals induced by TNF as an "autocrine cascade." Time-dependent crosstalk of synergistic and antagonistic autocrine circuits may serve to link cellular responses to the local environment.
Janes
Kevin A
KA
Center for Cell Decision Processes, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Gaudet
Suzanne
S
Albeck
John G
JG
Nielsen
Ulrik B
UB
Lauffenburger
Douglas A
DA
Sorger
Peter K
PK
D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D019295:Computational Biology; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D006133:Growth Substances / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D008954:Models, Biological; D020239:Receptor Cross-Talk / Q000502:physiology; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
D006133:Growth Substances; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha