Mutations in the adaptor protein PSTPIP2 are the cause of the autoinflammatory disease chronic multifocal osteomyelitis in mice. This disease closely resembles the human disorder chronic recurrent multifocal osteomyelitis, characterized by sterile inflammation of the bones and often associated with inflammation in other organs, such as the skin. The most critical process in the disease's development is the enhanced production of IL-1β. This excessive IL-1β is likely produced by neutrophils. In addition, the increased activity of macrophages, osteoclasts, and megakaryocytes has also been described. However, the molecular mechanism of how PSTPIP2 deficiency results in this phenotype is poorly understood. Part of the PSTPIP2 inhibitory function is mediated by protein tyrosine phosphatases from the proline-, glutamic acid-, serine- and threonine-rich (PEST) family, which are known to interact with the central part of this protein, but other regions of PSTPIP2 not required for PEST-family phosphatase binding were also shown to be indispensable for PSTPIP2 function. In this article, we show that PSTPIP2 binds the inhibitory enzymes Csk and SHIP1. The interaction with SHIP1 is of particular importance because it binds to the critical tyrosine residues at the C terminus of PSTPIP2, which is known to be crucial for its PEST-phosphatase-independent inhibitory effects in different cellular systems. We demonstrate that in neutrophils this region is important for the PSTPIP2-mediated suppression of IL-1β processing and that SHIP1 inhibition results in the enhancement of this processing. We also describe deregulated neutrophil response to multiple activators, including silica, Ab aggregates, and LPS, which is suggestive of a rather generalized hypersensitivity of these cells to various external stimulants.

• MeSH
• adaptorové proteiny signální transdukční genetika   imunologie   metabolismus   MeSH
• buněčné linie MeSH
• C-terminální Src kinasa MeSH
• cytoskeletální proteiny genetika   imunologie   metabolismus   MeSH
• fosfatasy antagonisté a inhibitory   imunologie   metabolismus   MeSH
• fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy MeSH
• fosforylace MeSH
• inositolpolyfosfát-5-fosfatasy MeSH
• interleukin-1beta biosyntéza   MeSH
• makrofágy imunologie   MeSH
• megakaryocyty imunologie   MeSH
• molekulární sekvence - údaje MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• neutrofily imunologie   MeSH
• osteoklasty imunologie   MeSH
• osteomyelitida genetika   imunologie   MeSH
• sekvence aminokyselin MeSH
• signální transdukce imunologie   MeSH
• skupina kinas odvozených od src-genu imunologie   MeSH
• tyrosinkinasy metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zánět imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• C-terminální Src kinasa MeSH
• CSK protein, human MeSH Prohlížeč
• cytoskeletální proteiny MeSH
• fosfatasy MeSH
• fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy MeSH
• IL1B protein, mouse MeSH Prohlížeč
• inositolpolyfosfát-5-fosfatasy MeSH
• INPP5D protein, human MeSH Prohlížeč
• Inpp5d protein, mouse MeSH Prohlížeč
• interleukin-1beta MeSH
• Pstpip2 protein, mouse MeSH Prohlížeč
• skupina kinas odvozených od src-genu MeSH
• tyrosinkinasy MeSH

High-level leukemia cell expression of micro-RNA 155 (miR-155) is associated with more aggressive disease in patients with chronic lymphocytic leukemia (CLL), including those cases with a low-level expression of ζ-chain-associated protein of 70 kD. CLL with high-level miR-155 expressed lower levels of Src homology-2 domain-containing inositol 5-phosphatase 1 and were more responsive to B-cell receptor (BCR) ligation than CLL with low-level miR-155. Transfection with miR-155 enhanced responsiveness to BCR ligation, whereas transfection with a miR-155 inhibitor had the opposite effect. CLL in lymphoid tissue expressed higher levels of miR155HG than CLL in the blood of the same patient. Also, isolated CD5(bright)CXCR4(dim) cells, representing CLL that had been newly released from the microenvironment, expressed higher levels of miR-155 and were more responsive to BCR ligation than isolated CD5(dim)CXCR4(bright) cells of the same patient. Treatment of CLL or normal B cells with CD40-ligand or B-cell-activating factor upregulated miR-155 and enhanced sensitivity to BCR ligation, effects that could be blocked by inhibitors to miR-155. This study demonstrates that the sensitivity to BCR ligation can be enhanced by high-level expression of miR-155, which in turn can be induced by crosstalk within the tissue microenvironment, potentially contributing to its association with adverse clinical outcome in patients with CLL.

• MeSH
• antigeny CD5 genetika   metabolismus   MeSH
• chronická lymfatická leukemie genetika   mortalita   patologie   MeSH
• dospělí MeSH
• fosfatasy genetika   metabolismus   MeSH
• inositolpolyfosfát-5-fosfatasy MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• ligand CD40 genetika   metabolismus   MeSH
• messenger RNA genetika   MeSH
• mikro RNA genetika   MeSH
• míra přežití MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádorové mikroprostředí MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• prognóza MeSH
• protein-tyrosinkináza ZAP-70 genetika   metabolismus   MeSH
• průtoková cytometrie MeSH
• receptory antigenů B-buněk genetika   metabolismus   MeSH
• receptory CXCR4 genetika   metabolismus   MeSH
• regulace genové exprese u leukemie * MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální transdukce MeSH
• vápník metabolismus   MeSH
• western blotting MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antigeny CD5 MeSH
• fosfatasy MeSH
• inositolpolyfosfát-5-fosfatasy MeSH
• ligand CD40 MeSH
• messenger RNA MeSH
• mikro RNA MeSH
• MIRN155 microRNA, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• protein-tyrosinkináza ZAP-70 MeSH
• receptory antigenů B-buněk MeSH
• receptory CXCR4 MeSH
• vápník MeSH
• ZAP70 protein, human MeSH Prohlížeč