Network dynamics determine the autocrine and paracrine signaling functions of TNF

25Citations
Citations of this article
71Readers
Mendeley users who have this article in their library.
Get full text

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 NFkB 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 NFkB response, although it plays a potent paracrine role in neighboring cells. However, in response to CpG DNA, autocrine TNF extends the duration of NFkB 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.

Cite

CITATION STYLE

APA

Caldwell, A. B., Birnbaum, H. A., Cheng, Z., Hoffmann, A., & Vargas, J. D. (2014). Network dynamics determine the autocrine and paracrine signaling functions of TNF. Genes and Development, 28(19), 2120–2133. https://doi.org/10.1101/gad.244749.114

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free