Study Title:

TNFa Signalling is key to Ramping Up Your Immune Response

Study Abstract

Cytokines are protein messengers that act to modulate the differentiation or activation of their target cells. Bone marrow macrophages can become activated tissue macrophages, dendritic cells, or osteoclasts depending on to which cytokines they are exposed. However, one cytokine can often induce divergent outcomes, suggesting that other signals are needed to establish the specificity of the result. We hypothesize that these signals may derive from the local environment and serve to prime cells to respond toward a specific outcome. Here, it is shown that the cytokine TNF- is capable of affecting the fate of macrophages by upregulating the NADase CD38. CD38 upregulation primes macrophages, such that signals induced by inflammatory stimuli are augmented, while those leading to osteoclast formation are inhibited. We show that TNF- -induced CD38 expression negatively affects the expression of osteoclast markers, while it enhances inflammatory gene expression by decreasing ERK1/2 phosphorylation and increasing NF- B activation. Furthermore, it is shown that CD38 may reduce osteoclastogenesis and increase inflammatory gene induction by decreasing cellular histone deacetylase activity. These results provide a demonstration of how a cytokine can prime cells to differentiate toward a certain lineage or acquire enhanced activation characteristics. Since CD38 is an ectoenzyme, we suggest that the modulation of extracellular NAD+ metabolism likely serves as a unique mechanism to coordinate the fate of cells within a local environment.
Priming of adaptive immune responses, as well as enhancement of innate immunity, occurs through the production of cytokines by cells of the innate immune system. Exposure of T lymphocytes to the proinflammatory cytokine TNF- allows rapid production of IL-2 and interferon- mRNA, enabling cytokine-primed cells to achieve quicker and higher levels of these cytokines in response to a subsequent exposure). Priming by TNF- occurs partly through alterations in signal transduction pathways, such as NF- B, and partly through increases in the production of proinflammatory autocrine/paracrine stimulants, such as interferon- .

Study Information

Iqbal J, Zaidi M.
CD38 is required for priming by TNF-alpha: a mechanism for extracellular coordination of cell fate.
Am J Physiol Renal Physiol
2007 April
Mount Sinai Bone Program, Mount Sinai School of Medicine, Box 1055, 1 Gustave Levy Place, New York, NY 10029, USA

Full Study

http://ajprenal.physiology.org/cgi/content/full/292/4/F1283