To successfully feed, ticks inject pharmacoactive molecules into the vertebrate host including cystatin cysteine protease inhibitors. However, the molecular and cellular events modulated by tick saliva remain largely unknown. Here, we describe and characterize a novel immunomodulatory cystatin, Iristatin, which is upregulated in the salivary glands of feeding Ixodes ricinus ticks. We present the crystal structure of Iristatin at 1.76 Å resolution. Purified recombinant Iristatin inhibited the proteolytic activity of cathepsins L and C and diminished IL-2, IL-4, IL-9, and IFN-γ production by different T-cell populations, IL-6 and IL-9 production by mast cells, and nitric oxide production by macrophages. Furthermore, Iristatin inhibited OVA antigen-induced CD4+ T-cell proliferation and leukocyte recruitment in vivo and in vitro. Our results indicate that Iristatin affects wide range of anti-tick immune responses in the vertebrate host and may be exploitable as an immunotherapeutic.

• Klíčová slova
• Cathepsin, Crystal structure, Immune responses, Ixodes ricinus, Saliva,
• MeSH
• cystatiny klasifikace   genetika   farmakologie   MeSH
• cytokiny metabolismus   MeSH
• epoxidové sloučeniny metabolismus   MeSH
• fylogeneze MeSH
• imunosupresiva chemie   metabolismus   farmakologie   MeSH
• klíště chemie   genetika   metabolismus   MeSH
• krystalografie rentgenová MeSH
• makrofágy účinky léků   metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• proteiny členovců chemie   genetika   farmakologie   MeSH
• proteolýza účinky léků   MeSH
• sekvence aminokyselin MeSH
• sekvenční homologie aminokyselin MeSH
• slinné cystatiny chemie   genetika   farmakologie   MeSH
• T-lymfocyty účinky léků   metabolismus   MeSH
• tyrosin analogy a deriváty   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cathestatin C MeSH Prohlížeč
• cystatiny MeSH
• cytokiny MeSH
• epoxidové sloučeniny MeSH
• imunosupresiva MeSH
• oxid dusnatý MeSH
• proteiny členovců MeSH
• slinné cystatiny MeSH
• tyrosin MeSH

Bone marrow-derived mesenchymal stem cells (MSCs) modulate immune response and can produce significant levels of transforming growth factor-β (TGF-β) and interleukin-6 (IL-6). These 2 cytokines represent the key factors that reciprocally regulate the development and polarization of naive T-cells into regulatory T-cell (Treg) population or proinflammatory T helper 17 (Th17) cells. In the present study we demonstrate that MSCs and their products effectively regulate expression of transcription factors Foxp3 and RORγt and control the development of Tregs and Th17 cells in a population of alloantigen-activated mouse spleen cells or purified CD4(+)CD25(-) T-cells. The immunomodulatory effects of MSCs were more pronounced when these cells were stimulated to secrete TGF-β alone or TGF-β together with IL-6. Unstimulated MSCs produce TGF-β, but not IL-6, and the production of TGF-β can be further enhanced by the anti-inflammatory cytokines IL-10 or TGF-β. In the presence of proinflammatory cytokines, MSCs secrete significant levels of IL-6, in addition to a spontaneous production of TGF-β. MSCs producing TGF-β induced preferentially expression of Foxp3 and activation of Tregs, whereas MSC supernatants containing TGF-β together with IL-6 supported RORγt expression and development of Th17 cells. The effects of MSC supernatants were blocked by the inclusion of neutralization monoclonal antibody anti-TGF-β or anti-IL-6 into the culture system. The results showed that MSCs represent important players that reciprocally regulate the development and differentiation of uncommitted naive T-cells into anti-inflammatory Foxp3(+) Tregs or proinflammatory RORγt(+) Th17 cell population and thereby can modulate autoimmune, immunopathological, and transplantation reactions.

• MeSH
• buněčná diferenciace imunologie   MeSH
• buněčné kultury MeSH
• cytokiny biosyntéza   MeSH
• imunita MeSH
• kultivační média speciální farmakologie   MeSH
• mezenchymální kmenové buňky fyziologie   MeSH
• myši MeSH
• parakrinní signalizace imunologie   MeSH
• regulační T-lymfocyty imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• zánět imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• kultivační média speciální MeSH