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Genes Dev. 2014 Oct 1;28(19):2120-33. doi: 10.1101/gad.244749.114.

Network dynamics determine the autocrine and paracrine signaling functions of TNF.

Author information

1
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;
2
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.
3
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.

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.

KEYWORDS:

MAP kinase; NFκB; inflammation; innate immune response; pathogen sensors

PMID:
25274725
PMCID:
PMC4180974
DOI:
10.1101/gad.244749.114
[Indexed for MEDLINE]
Free PMC Article

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