A selective novel low-molecular-weight inhibitor of IkappaB kinase-beta (IKK-beta) prevents pulmonary inflammation and shows broad anti-inflammatory activity
| Autor: | Karl, Ziegelbauer, Florian, Gantner, Nicholas W, Lukacs, Aaron, Berlin, Kinji, Fuchikami, Toshiro, Niki, Katsuya, Sakai, Hisayo, Inbe, Keisuke, Takeshita, Mina, Ishimori, Hiroshi, Komura, Toshiki, Murata, Timothy, Lowinger, Kevin B, Bacon |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Transcriptional Activation Pyridines Protein Serine-Threonine Kinases Mice NF-KappaB Inhibitor alpha Cell Movement Cell Line Tumor Oxazines Leukocytes Animals Edema Humans Phosphorylation Rats Wistar Cell Proliferation Mice Inbred BALB C Tumor Necrosis Factor-alpha Anti-Inflammatory Agents Non-Steroidal NF-kappa B Pneumonia I-kappa B Kinase Rats Papers Female I-kappa B Proteins Cell Adhesion Molecules Signal Transduction |
| Zdroj: | British journal of pharmacology. 145(2) |
| ISSN: | 0007-1188 |
| Popis: | 1 Pulmonary inflammatory diseases such as asthma are characterized by chronic, cell-mediated inflammation of the bronchial mucosa. 2 Recruitment and activation of inflammatory cells is orchestrated by a variety of mediators such as cytokines, chemokines, or adhesion molecules, the expression of which is regulated via the transcription factor nuclear factor kappa B (NF-kappaB). 3 NF-kappaB signaling is controlled by the inhibitor of kappa B kinase complex (IKK), a critical catalytic subunit of which is IKK-beta. 4 We identified COMPOUND A as a small-molecule, ATP-competitive inhibitor selectively targeting IKK-beta kinase activity with a K(i) value of 2 nM. 5 COMPOUND A inhibited stress-induced NF-kappaB transactivation, chemokine-, cytokine-, and adhesion molecule expression, and T- and B-cell proliferation. 6 COMPOUND A is orally bioavailable and inhibited the release of LPS-induced TNF-alpha in rodents. 7 In mice COMPOUND A inhibited cockroach allergen-induced airway inflammation and hyperreactivity and efficiently abrogated leukocyte trafficking induced by carrageenan in mice or by ovalbumin in a rat model of airway inflammation. 8 COMPOUND A was well tolerated by rodents over 3 weeks without affecting weight gain. 9 Furthermore, in mice COMPOUND A suppressed edema formation in response to arachidonic acid, phorbol ester, or edema induced by delayed-type hypersensitivity. 10 These data suggest that IKK-beta inhibitors offer an effective therapeutic approach for inhibiting chronic pulmonary inflammation. |
| Databáze: | OpenAIRE |
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