title: Network dynamics determine the autocrine and paracrine signaling functions of TNF.
abstract: A hallmark of the inflammatory response to pathogen exposure is the production of tumor necrosis factor (TNF) that coordinates innate and adaptive immune responses by functioning in an autocrine or paracrine manner. Numerous molecular mechanisms contributing to TNF production have been identified, but how they function together in macrophages remains unclear. Here, we pursued an iterative systems biology approach to develop a quantitative understanding of the regulatory modules that control TNF mRNA synthesis and processing, mRNA half-life and translation, and protein processing and secretion. By linking the resulting model of TNF production to models of the TLR-, the TNFR-, and the NFκB signaling modules, we were able to study TNF's functions during the inflammatory response to diverse TLR agonists. Contrary to expectation, we predicted and then experimentally confirmed that in response to lipopolysaccaride, TNF does not have an autocrine function in amplifying the NFκB response, although it plays a potent paracrine role in neighboring cells. However, in response to CpG DNA, autocrine TNF extends the duration of NFκB activity and shapes CpG-induced gene expression programs. Our systems biology approach revealed that network dynamics of MyD88 and TRIF signaling and of cytokine production and response govern the stimulus-specific autocrine and paracrine functions of TNF.
authors.affiliation: Signaling Systems Laboratory, Department of Chemistry and Biochemistry, and San Diego Center for Systems Biology, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Caldwell
authors.affiliation: Signaling Systems Laboratory, Department of Chemistry and Biochemistry, and San Diego Center for Systems Biology, University of California at San Diego, La Jolla, California 92093, USA; Institute for Quantitative and Computational Biosciences, Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California 90025, USA.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Signaling Systems Laboratory, Department of Chemistry and Biochemistry, and San Diego Center for Systems Biology, University of California at San Diego, La Jolla, California 92093, USA; Institute for Quantitative and Computational Biosciences, Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California 90025, USA.
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Vargas
authors.affiliation: Signaling Systems Laboratory, Department of Chemistry and Biochemistry, and San Diego Center for Systems Biology, University of California at San Diego, La Jolla, California 92093, USA; Institute for Quantitative and Computational Biosciences, Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California 90025, USA.
authors.forename: Harry A
authors.initials: HA
authors.lastname: Birnbaum
authors.affiliation: Signaling Systems Laboratory, Department of Chemistry and Biochemistry, and San Diego Center for Systems Biology, University of California at San Diego, La Jolla, California 92093, USA; Institute for Quantitative and Computational Biosciences, Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California 90025, USA ahoffmann@ucla.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D005786:Gene Expression Regulation; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology*; D015398:Signal Transduction; D049490:Systems Biology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C476286:Ticam1 protein, mouse
keywords: MAP kinase; NFκB; inflammation; innate immune response; pathogen sensors