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- Andersson, Mattias K., et al.
(författare)
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The extended substrate cleavage specificity of the human mast cell chymase reveals a serine protease with well-defined substrate recognition profile
- 2009
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 0953-8178 .- 1460-2377. ; 21:1, s. 95-104
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Tidskriftsartikel (refereegranskat)abstract
- The human chymase (HC) is a major granule constituent of mast cells (MCs) residing in the connective tissue and the sub-mucosa. Although many potential substrates have been described for this important MC enzyme, its full range of in vivo substrates has most likely not yet been identified. A major step toward a better understanding of the function of the HC is therefore to determine its extended cleavage specificity. Using a phage-displayed random nonapeptide library, we show that the HC has a rather stringent substrate recognition profile. Only aromatic amino acids (aa) are accepted in position P1, with a strong preference for Tyr and Phe over Trp. Aliphatic aa are preferred in positions P2 to P4 N-terminal of the cleaved bond. In the P1' position C-terminal of the cleaved bond, Ser is clearly over-represented and acidic aa Asp and Glu are strongly preferred in the P2' position. In P3', the small aliphatic aa Ala, Val and Gly were frequently observed. The consensus sequence, from P4 to P3': Gly/Leu/Val-Val/Ala/Leu-Ala/Val/Leu-Tyr/Phe-Ser-Asp/Glu-Ala/Val/Gly, provides an instrument for the identification of novel in vivo substrates for the HC. Interestingly, a very similar cleavage specificity was recently reported for the major chymase in mouse connective tissue mast cells (CTMCs), the beta-chymase mouse mast cell protease-4, suggesting functional homology between these two enzymes. This indicates that a rather stringent chymotryptic substrate recognition profile has been evolutionary conserved for the dominant CTMC chymase in mammals.
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- Cai, Yan, et al.
(författare)
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Infliximab alleviates inflammation and ex vivo airway hyperreactivity in asthmatic E3 rats
- 2011
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 1460-2377 .- 0953-8178. ; 23:7, s. 443-451
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Tidskriftsartikel (refereegranskat)abstract
- Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of asthma, and neutralization of TNF-alpha is an effective therapy for inflammatory diseases. The present study tested the idea that a TNF-alpha antibody, infliximab, may be useful in the management of asthma. E3 rats were immunized with ovalbumin (OVA)/alum and received infliximab intra-peritoneally. Two weeks later, OVA-PBS was instilled intranasally daily for 7 days. Bronchoalveolar lavage fluids (BALFs), serum and lung homogenates were collected for analysis of cells and inflammatory mediators. Contractile responses of lobar-bronchus segments to agonists were functionally tested. Pulmonary tissues were investigated using histological examination. The results showed that the sensitized 'model E3 rats' exhibited an increase in the total amount of inflammatory cells, primarily eosinophils, in BALF and pulmonary tissue, as well as epithelial damage. Serum levels of IgE increased and so did the levels of nitric oxide, inducible nitric oxide synthase, TNF-alpha and IL-4, IL-5 and IL-13 in lung homogenate and serum. Furthermore, the contractile responses in bronchi induced by endothelin-1, sarafotoxin 6c and bradykinin increased and isoprenaline-induced relaxations decreased. All these changes induced by the sensitization procedure were reduced by the infliximab treatment. The results suggest that infliximab prevents the development of local airway inflammation and antagonizes changes of the bronchial smooth muscle receptor phenotype, thereby blocking the development of airway smooth muscle hyperreactivity of asthmatic rats.
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- Eberhardson, Michael, et al.
(författare)
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The brain-gut axis, inflammatory bowel disease and bioelectronic medicine
- 2021
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Ingår i: International Immunology. - : OXFORD UNIV PRESS. - 0953-8178 .- 1460-2377. ; 33:6, s. 349-356
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Forskningsöversikt (refereegranskat)abstract
- The hallmark of inflammatory bowel diseases (IBD) is chronic intestinal inflammation with typical onset in adolescents and young adults. An abundance of neutrophils is seen in the inflammatory lesions, but adaptive immunity is also an important player in the chronicity of the disease. There is an unmet need for new treatment options since modern medicines such as biological therapy with anti-cytokine antibodies still leave a substantial number of patients with persisting disease activity. The role of the central nervous system and its interaction with the gut in the pathophysiology of IBD have been brought to attention both in animal models and in humans after the discovery of the inflammatory reflex. The suggested control of gut immunity by the brain-gut axis represents a novel therapeutic target suitable for bioelectronic intervention. In this review, we discuss the role of the inflammatory reflex in gut inflammation and the recent advances in the treatment of IBD by intervening with the brain-gut axis through bioelectronic devices.
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