title: Deciphering signaling outcomes from a system of complex networks.
abstract: Cellular signal transduction machinery integrates information from multiple inputs to actuate discrete cellular behaviors. Interaction complexity exists when an input modulates the output behavior that results from other inputs. To address whether this machinery is iteratively complex--that is, whether increasing numbers of inputs produce exponential increases in discrete cellular behaviors--we examined the modulated secretion of six cytokines from macrophages in response to up to five-way combinations of an agonist of Toll-like receptor 4, three cytokines, and conditions that activated the cyclic adenosine monophosphate pathway. Although all of the selected ligands showed synergy in paired combinations, few examples of nonadditive outputs were found in response to higher-order combinations. This suggests that most potential interactions are not realized and that unique cellular responses are limited to discrete subsets of ligands and pathways that enhance specific cellular functions.
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hsueh
authors.forename: Madhusudan
authors.initials: M
authors.lastname: Natarajan
authors.forename: Iain
authors.initials: I
authors.lastname: Fraser
authors.forename: Blake
authors.initials: B
authors.lastname: Pond
authors.forename: Jamie
authors.initials: J
authors.lastname: Liu
authors.forename: Susanne
authors.initials: S
authors.lastname: Mumby
authors.forename: Heping
authors.initials: H
authors.lastname: Han
authors.forename: Lily I
authors.initials: LI
authors.lastname: Jiang
authors.forename: Melvin I
authors.initials: MI
authors.lastname: Simon
authors.forename: Ronald
authors.initials: R
authors.lastname: Taussig
authors.forename: Paul C
authors.initials: PC
authors.lastname: Sternweis
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D054405:Chemokine CCL3 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013400:Sugar Acids / Q000494:pharmacology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D054405:Chemokine CCL3; D018946:Chemokine CCL5; D016207:Cytokines; D015850:Interleukin-6; D012333:RNA, Messenger; D013400:Sugar Acids; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C002532:2-keto-3-deoxyoctonate; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor; D015124:8-Bromo Cyclic Adenosine Monophosphate; D016899:Interferon-beta; D007545:Isoproterenol