Trends in Immunology
Volume 32, Issue 8, August 2011, Pages 380-387
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Review
ADAM17: a molecular switch to control inflammation and tissue regeneration

https://doi.org/10.1016/j.it.2011.05.005Get rights and content

A disintegrin and metalloproteinase 17 (ADAM17), also known as tumor necrosis factor-α converting enzyme (TACE), is a membrane-bound enzyme that cleaves cell surface proteins, such as cytokines (e.g. TNFα), cytokine receptors (e.g. IL-6R and TNF-R), ligands of ErbB (e.g. TGFα and amphiregulin) and adhesion proteins (e.g. L-selectin and ICAM-1). Here we examine how ectodomain shedding of these molecules can alter their biology and impact on immune and inflammatory responses and cancer development. Gene targeting of Adam17 is embryonic lethal, highlighting the importance of ectodomain shedding during development. Tissue-specific deletion, or hypomorphic knock-in, of Adam17 demonstrates an in vivo role for ADAM17 in controlling inflammation and tissue regeneration. The potential of ADAM17 as therapeutic target is also discussed.

Section snippets

The A disintegrin and metalloproteinase (ADAM17) is the prototype of the ADAM family of ectodomain shedding proteases

It is estimated that on platelets, up to 10% of all cell surface proteins are proteolytically cleaved and released into the extracellular space; this percentage is likely to be in the same range for all somatic cells via a process called ectodomain shedding [1]. Shedding of integral membrane proteins is observed mostly for type I and type II transmembrane or GPI-anchored proteins and the cleavage site is generally located in close proximity to the outer surface of the cell membrane. Ectodomain

ADAM17 function in the immune system

Inflammation is characterized by elevated levels of cytokines such as TNFα and IL-6. As outlined below, ADAM17 impacts the biology of TNFα and IL-6, which led to the speculation that inhibition of this metalloprotease might have beneficial effects in autoimmune diseases [6].

In the mouse, blockade of TNFα or inhibition of TNFα shedding results in survival of otherwise lethal LPS-induced septic shock [7]. Unfortunately, use of neutralizing anti-TNFα monoclonal antibodies (mAbs) in clinical trials

ADAM17 and cancer

ErbB signaling is involved in the growth of many tumors 28, 29. ADAM17 is upregulated in most tumor cells [28]. In a process called transactivation, shedding of ErbB ligands, e.g. from epithelial cells (Figure 2), by ADAM17 (Table 1) is necessary for appropriate stimulation of ErbB [30]. ADAM17-mediated shedding of ErbB ligands is required for growth of lung carcinoma cells. Surprisingly, on the same cells ADAM17 cleaves Notch1 and the subsequent γ-secretase-mediated release of the

Studying ADAM17 activity in vivo

ADAM17-deficient mice have defects in the mammary epithelium, vascular system, lung, eye, hair, heart and skin and as a result die between embryonic day 17.5 and the first few days after birth [36]. This is reminiscent of ErbB ligand-deficient mice, indicating the importance of the ADAM17−ErbB axis during development [36]. The small subpopulation of ADAM17-deficient mice that survive have reduced lymphocyte numbers, impaired T and B cell development, reduced body weight and an overall

Regulation of ADAM17 activity

Given the importance of cytokine and cytokine receptor shedding for activation of the immune system, it is important to understand how shedding is regulated at the cellular level (reviewed in [45]). ADAM17 is expressed and upregulated in tumor cells almost ubiquitously; however, the involvement of the tumor microenvironment for regulation of ADAM17 expression is not known.

The phorbol ester phorbol 12-myristate 13-acetate (PMA) is a potent activator of ADAM17. PMA induces phosphorylation of PKC

Concluding remarks: ADAM17 and control of inflammatory and regenerative responses

Activation of ADAM17 is activated by signals such as MAP kinases, PKCs and activated oncogenes. Activated ADAM17 is capable of controlling pathways that are biologically distinct. On one hand, cleavage of substrates, including TNFα, IL-6R and L-selectin, can be considered pro-inflammatory because they stimulate both innate and acquired immune responses (Figure 3). On the other hand, activation of the ErbB pathway via trans-activation and via Notch1 cleavage has different consequences (Figure 3

Acknowledgments

The work described in this Review was funded by grants from the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB841, project C1 and SFB877, project A1 and A2) and by the Cluster of Excellence ‘Inflammation at Interfaces’.

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