NK - Cytokiinit - NKG2D akselista ADAM17 aktiivisuus lisääntyy ja TNF-alfaa vapautuu.
J Immunol. 2017 Oct 15;199(8):2865-2872. doi: 10.4049/jimmunol.1700647. Epub 2017 Sep 11.
NKG2D Signaling between Human NK Cells Enhances TACE-Mediated TNF-α Release.
NK
group 2 member D (NKG2D) is a strong NK cell-activating receptor, with
engagement by ligands triggering granule release and cytokine
production. The function of NKG2D signaling in NK cells has largely been
studied in the context of engagement of the receptor by ligands
expressed on the surface of target cells. We report that upon activation
with IL-12, IL-15, and IL-18 human NK cells express NKG2D ligands of
the UL16 binding protein family on the cell surface. NKG2D-ligand
interaction between cytokine-stimulated NK cells increases the activity
of the metalloprotease TNF-α-converting enzyme (ADAM 17/TACE) . This enhanced
TNF-α-converting enzyme activity significantly increases the release of
TNF-α and UL16 binding protein from the surface of the NK cells. These
results demonstrate that NKG2D signaling is critical for maximal TNF-α
release by NK cells. Further, they demonstrate a role for NKG2D-ligand
interaction via homotypic NK cell contact in NK cell effector function. Copyright © 2017 by The American Association of Immunologists, Inc.
2018
https://www.sciencedirect.com/science/article/pii/S0167488917301878#t0005
1. Introduction
It was discovered in 1988 that the pro-inflammatory mediator tumor necrosis factor alpha (TNFα) was synthesized as a transmembrane protein, which needs to be proteolytically cleaved to be systemically active [1]. Since then, many researchers tried to identify the responsible proteolytic activity, which was believed to be an important therapeutic target.
In 1994, it was reported that the TNFα
cleaving enzyme was a metalloprotease (MMP), which could be inhibited by
hydroxamic acid compounds. This hydroxamate not only reduced LPS-induced
TNFα levels in vivo but also rescued mice from lethal septic shock confirming the TNFα cleaving enzyme being a promising therapeutic target [2].
(1997 ) Three years later, cDNAs coding for human and murine TNFα cleaving enzyme were cloned [3], [4], which showed that the enzyme is a membrane bound metalloprotease (MT-MMP) , which belonged to the family of disintegrin metalloproteases called adamalysins or ADAMs [5]. Subsequently, the TNFα cleaving enzyme was renamed ADAM17 [5].
ADAM17 knock-out animals turned out not to be viable [6]. Moreover, they showed an open eye phenotype at birth, which was reminiscent of mice lacking transforming growth factor alpha (TGFα), a ligand of the epidermal growth factor receptor (EGF-R). Since all ligands of the EGF-R are transmembrane proteins, which need to be cleaved in order to act systemically [7] it was hypothesized that ligands of the EGF-R were substrates of ADAM17 [6]. This was supported by data indicating that l-selectin, IL-6R and TGFα were processed by the same protease [8]. Meanwhile we know that ADAM17 has more than 80 substrates ranging from cytokines, growth factors, receptors to many cell adhesion molecules (Table 1) [9].
Therefore, it is not surprising that the biology of ADAM17 is complex
and the protease is involved in the regulation of many body functions
and developmental processes.
2. The shedding enzyme ADAM17
At least 10% of all cell surface proteins are believed to be proteolytically cleaved leading to the release of soluble proteins [10], [11]. As outlined above, ADAM17 was the first shedding protease to be molecularly characterized and it was shown to consist of an N-terminal signal sequence followed by a pro-domain, a metalloproteinase or catalytic domain, a disintegrin domain, a cysteine-rich membrane proximal domain, a single transmembrane domain and a cytoplasmic portion (Fig. 1) [3], [4].
| Immune system | Development, differentiation | Cell adhesion | Others |
|---|---|---|---|
| IL-1RII | TGFα | ALCAM | ACE-2 |
| IL-6R | Hb-EGF | CD44 | APP |
| IL-15R | AREG | CD62L (L-selectin) | APP-like protein2 |
| CX3CL1 (fractalkine) | Epigen | Collagen XVII | Carbonic hydrolase 9 |
| M-CSFR | EREG | Desmoglein 2 | Prion protein |
| TNF-RI | NRG1 | EpCam | Ebola virus glycoprotein |
| TNF-RII | FLT-3L | ICAM-1 | EPCR |
| LDL-R | KL-1 | JAM-A | GPIba |
| SORL1 | KL-2 | L1-CAM | GPV |
| SORT1 | Jagged | NCAM | GPVI |
| SORCS1 | DLL1 | Nectin-4 | Klotho |
| SORCS3 | Notch1 | SynCAM1 | Muc-1, Episialin |
| TNFα | GH-R | VACM-1 | NPR |
| Lymphotoxin α | IGF2-R | Pre-adipocyte factor | |
| RANKL (TRANCE) | HER4 (ErbB4) | Ptprz | |
| CSF-1 | TrkA | ||
| TIM-1 | VEGF-R2 | ||
| TIM-3 | LYPD3 | ||
| TIM-4 | PMEL17 | ||
| MIC-A | PTP-LAR | ||
| MIC-B | SEMA4D | ||
| LAG-3 | Syndecan1 | ||
| CD16 | Syndecan4 | ||
| CD30 (TNFRSF8) | TEMEFF2 | ||
| CD36 | Vasorin | ||
| CD40 (TNFRSF5) | |||
| CD89 | |||
| CD91 (APOER) | |||
| CD163 | |||
| ICOS-L |
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