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 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 stimulusspecific autocrine and paracrine functions of TNF.

Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages

“…Like IFNα, TNFα was predicted to be involved in an autocrine loop in MDM elicited by LPS, since the TNFα receptor is also induced 27. Our data (Supplemental Table S2) confirm and extend evidence of autocrine TNFα signaling as a feed‐forward activator of macrophage gene expression30, 62, 63 and identify the subset of inducible genes dependent upon that stimulus. The lack of impact of anti‐TNFα on LPS‐inducible IDO1 may reflect the magnitude of the response.…”

“…Alternatively, activation of IDO1 by IFN‐γ requires co‐stimulation by TNFα, which increases the occupancy of IFN‐response elements 64, 65. It may be that LPS provides this second signal independently of TNFα 30, 62, 63…”

Deciphering the genomic toolkit underlying animal-bacteria interactions – insights through the demosponge Amphimedon queenslandica

“…Cytokines like TNF and TGF-β trigger behavioural changes or differentiation of nearby celltypes through paracrine signalling in mammals (Derynck and Akhurst 2007;Caldwell, et al 2014), and the upregulation of these cytokines in my experiments suggests they too could participate in coordinating the sponge cellular response to bacteria. TNF in particular is upregulated in choanocytes compared to the other two cells types, and it is possible that choanocytes release TNF ligands to communicate with other cell-types in the vicinity of choanocyte chambers.…”

“…The MyD88-dependent pathway has an ancient, highly conserved role regulating humoral aspects of immunity through antimicrobial peptide (AMP) production in animals as diverse as Hydra, Drosophila and humans (Tauszig, et al 2000;). TNF signalling, on the other hand, is important for the coordination of cellular immunity through autocrine or paracrine signalling (Caldwell, et al 2014). Indeed, the Drosophila TNF ligand, Eiger, is an important modulator of phagocytic activity, and Eiger-mutant flies show decreased phagocytosis and thus reduced clearance of extracellular pathogens (Schneider, et al 2007).…”

Targeted therapeutics in inflammatory atherosclerosis

“…However, once monocytes adhere, they infiltrate into the lesions and differentiate into macrophages, which possess an inflammatory phenotype and secrete large amounts of proteases, inflammatory cytokines, reactive radicals, and auto-and paracrine signaling molecules [227][228][229]. These "flaring" molecules drive lesion remodeling, invasiveness (and metastasis in the case of cancer), and can induce a phenotypical change in preexisting macrophages and other cells [230][231][232]. Thus, preventing macrophage activation and dampening local inflammation by using nanomedicines to deliver anti-inflammatory drugs can induce a favorable phenotype [233].…”