Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite. In this article, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected. In addition, the expression of IL-1β and IRF4 is strongly reduced in the presence of sialostatin L. Correspondingly, IRF4- or IL-1R-deficient mast cells exhibit a strong impairment in IL-9 production, demonstrating the importance of IRF4 and IL-1 in the regulation of the Il9 locus in mast cells. Furthermore, IRF4 binds to the promoters of Il1b and Il9, suggesting that sialostatin L suppresses mast cell-derived IL-9 preferentially by inhibiting IRF4. In an experimental asthma model, mast cell-specific deficiency in IRF4 or administration of sialostatin L results in a strong reduction in asthma symptoms, demonstrating the immunosuppressive potency of tick-derived molecules.

• MeSH
• bronchiální astma genetika   imunologie   patologie   MeSH
• cystatiny imunologie   farmakologie   MeSH
• degranulace buněk imunologie   MeSH
• genetická transkripce MeSH
• imunosupresiva farmakologie   MeSH
• interakce hostitele a parazita imunologie   MeSH
• interferonové regulační faktory nedostatek   genetika   imunologie   MeSH
• interleukin-1beta genetika   imunologie   MeSH
• interleukin-6 genetika   imunologie   MeSH
• interleukin-9 antagonisté a inhibitory   genetika   imunologie   MeSH
• mastocyty účinky léků   imunologie   patologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• přirozená imunita účinky léků   MeSH
• promotorové oblasti (genetika) MeSH
• receptory interleukinu-1 genetika   imunologie   MeSH
• regulace genové exprese MeSH
• signální transdukce MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• cystatiny MeSH
• imunosupresiva MeSH
• interferon regulatory factor-4 MeSH Prohlížeč
• interferonové regulační faktory MeSH
• interleukin-1beta MeSH
• interleukin-6 MeSH
• interleukin-9 MeSH
• receptory interleukinu-1 MeSH
• sialostatin L, Ixodes scapularis MeSH Prohlížeč

Ticks developed a multitude of different immune evasion strategies to obtain a blood meal. Sialostatin L is an immunosuppressive cysteine protease inhibitor present in the saliva of the hard tick Ixodes scapularis. In this study, we demonstrate that sialostatin L strongly inhibits the production of IL-9 by Th9 cells. Because we could show recently that Th9-derived IL-9 is essentially involved in the induction of asthma symptoms, sialostatin L was used for the treatment of experimental asthma. Application of sialostatin L in a model of experimental asthma almost completely abrogated airway hyperresponsiveness and eosinophilia. Our data suggest that sialostatin L can prevent experimental asthma, most likely by inhibiting the IL-9 production of Th9 cells. Thus, alternative to IL-9 neutralization sialostatin L provides the basis for the development of innovative therapeutic strategies to treat asthma.

• MeSH
• bronchiální astma imunologie   metabolismus   prevence a kontrola   MeSH
• cystatiny imunologie   farmakologie   MeSH
• cytokiny imunologie   metabolismus   MeSH
• ELISA MeSH
• interleukin-9 biosyntéza   imunologie   MeSH
• Ixodidae imunologie   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• myši knockoutované MeSH
• myši MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• průtoková cytometrie MeSH
• separace buněk MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cystatiny MeSH
• cytokiny MeSH
• interleukin-9 MeSH
• sialostatin L, Ixodes scapularis MeSH Prohlížeč

STUDY OBJECTIVE: To examine the differences in the inflammatory cell and cytokine profile between patients with chronic bronchitis (CB) with and without airway obstruction compared to control subjects. DESIGN: We used bronchial biopsy samples from the patients and control subjects and analyzed them for the presence of CD3 T cells, CD68, major basic protein (MBP), elastase, and tryptase, as well as expression of messenger RNA (mRNA) coding for interleukin (IL)-4, IL-5, interferon (IFN)-gamma, IL-9, eotaxin, and IFN-gamma-inducible protein (IP)-10. The techniques of immunocytochemistry and in situ hybridization were used. Results were expressed as the number of immunoreactive and mRNA-positive cells per field. RESULTS: Increased number of elastase, CD68, and MBP-positive cells (n = 9, p < 0.01) was demonstrated in both groups of patients with CB compared to control subjects. In patients with CB and obstruction, the number of elastase, CD68, and the number of CD3-positive cells was significantly increased compared to patients with CB without obstruction (n = 9, p < 0.01). IFN-gamma mRNA expression was increased in both groups of patients with CB compared to control subjects (n = 9, p < 0.01). IL-9 mRNA was significantly increased only in patients with CB and obstruction (n = 9, p < 0.01). Co-localization studies demonstrated > 80% of all IL-9-positive cells to be CD3-positive T cells. IP-10 mRNA was significantly increased in both groups of patients with CB compared to control subjects (n = 9, p < 0.01). CONCLUSIONS: These results indicate a differential expression of inflammatory markers and cytokine mRNA in patients with obstructive CB. Increased presence of T lymphocytes and up-regulation of IL-9 and IP-10 mRNA expression in the bronchial biopsy samples may contribute to the airway obstruction in these patients.

• MeSH
• antigeny CD3 analýza   MeSH
• antigeny diferenciační myelomonocytární metabolismus   MeSH
• bronchy patologie   MeSH
• CD antigeny metabolismus   MeSH
• chemokin CCL11 MeSH
• chemokiny CC metabolismus   MeSH
• chronická bronchitida komplikace   metabolismus   patologie   MeSH
• chronická obstrukční plicní nemoc komplikace   metabolismus   patologie   MeSH
• cytokiny metabolismus   MeSH
• eozinofily patologie   MeSH
• hybridizace in situ MeSH
• imunohistochemie MeSH
• interleukin-9 biosyntéza   MeSH
• jehlová biopsie MeSH
• krevní proteiny metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• makrofágy patologie   MeSH
• neutrofily patologie   MeSH
• pankreatická elastasa metabolismus   MeSH
• proteiny eozinofilních granul MeSH
• ribonukleasy metabolismus   MeSH
• T-lymfocyty metabolismus   MeSH
• upregulace * MeSH
• zánět MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD3 MeSH
• antigeny diferenciační myelomonocytární MeSH
• CCL11 protein, human MeSH Prohlížeč
• CD antigeny MeSH
• CD68 antigen, human MeSH Prohlížeč
• chemokin CCL11 MeSH
• chemokiny CC MeSH
• cytokiny MeSH
• interleukin-9 MeSH
• krevní proteiny MeSH
• pankreatická elastasa MeSH
• proteiny eozinofilních granul MeSH
• ribonukleasy MeSH