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ABSTRACT: IL-17F plays a crucial role in airway inflammatory diseases including asthma, but its function has not been fully elucidated. CCL20 is also involved in allergic airway inflammation, while its regulatory mechanisms remain to be defined. To further identify a novel role of IL-17F, the expression of CCL20 by IL-17F in bronchial epithelial cells and the signaling mechanisms involved were investigated. Bronchial epithelial cells were stimulated with IL-17F, and the levels of CCL20 gene and protein measured, with the effects of the addition of various kinase inhibitors and siRNAs also investigated. IL-17F significantly induced the expression of CCL20 gene and protein. Pretreatment with inhibitors for MEK1/2, Raf1 and MSK1, and overexpression of a Raf1 dominant-negative mutant significantly diminished IL-17F-induced CCL20 production. Moreover, transfection of the siRNAs targeting MSK1, p90RSK, and CREB blocked CCL20 expression. These findings suggest that IL-17F is able to induce CCL20 via Raf1-MEK1/2-ERK1/2-MSK1/p90RSK-CREB signaling pathway in bronchial epithelial cells. The IL-17F/CCL20 axis may be a novel pharmacological target for asthma.
Journal of Allergy 01/2011; 2011:587204.
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ABSTRACT: A 52-year-old woman with advanced non-small cell lung cancer was admitted to our hospital with melena and palpable purpura which appeared on her lower legs. She had been taking gefitinib for about 2 months before admission. A skin biopsy revealed leukocytoclastic vasculitis in the superficial dermis and immunofluorescence also showed the presence of C3 depositions within the blood vessel walls, which led to a diagnosis of Henoch-Schönlein purpura. The purpura gradually improved with topical steroids and bed rest; however, gefitinib had to be discontinued because of a growing papulopustular rash with intense itching, and as a result of the discontinuation, both types of skin lesions resolved. Two months later, she resumed gefitinib treatment since her level of CEA began to rise. Even though the papulopustular rash developed after the readministration of gefitinib, there had been no evidence of Henoch-Schönlein purpura recurrence during 2.5 years follow-up. It has been reported that adult onset Henoch-Schönlein purpura is often associated with malignancy. This case, however, suggests that not only drug eruption but also paraneoplastic vasculitis should be considered in the differential diagnosis of palpable purpura in patients with non-small cell lung cancer receiving treatment with gefitinib.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 07/2010; 48(7):529-34.
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ABSTRACT: A new family of cytokines, the interleukin (IL)-17 family, has recently been defined, which reveals unique functions and distinct ligand-receptor signaling systems. This family contains six members, IL-17 (also called IL-17A), IL17B, IL-17C, IL-17D, IL-17E (IL-25) and IL-17F. The IL-17F gene was discovered in 2001, and is located on chromosome 6p12. Notably, among this family, IL-17F has been well characterized both in vitro and in vivo, and has been shown to have a pro-inflammatory role in asthma. IL-17F is clearly expressed in the airway of asthmatics and its expression level is correlated with disease severity. Moreover, a coding region variant (H161R) of the IL-17F gene is inversely associated with asthma and encodes an antagonist for the wild-type IL-17F. IL-17F is able to induce several cytokines, chemokines and adhesion molecules in bronchial epithelial cells, vein endothelial cells, fibroblasts and eosinophils. IL-17F utilizes IL-17RA and IL-17RC as its receptors, and activates the MAP kinase related pathway. IL-17F is derived from several cell types such as Th17 cells, mast cells and basophils, and shows a wide tissue expression pattern including lung. Overexpression of IL-17F gene in the airway of mice is associated with airway neutrophilia, the induction of many cytokines, an increase in airway hyperreactivity, and mucus hypersecretion. Hence, IL-17F may have a crucial role in allergic airway inflammation, and have important therapeutic implications in asthma.
Inflammation & allergy drug targets. 12/2009; 8(5):383-9.
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ABSTRACT: IL-17F is involved in asthma, but its biological function and signaling pathway have not been fully elucidated. IL-11 is clearly expressed in the airway of patients with allergic airway diseases such as asthma and plays an important role in airway remodeling and inflammation. Therefore, we investigated the expression of IL-11 by IL-17F in bronchial epithelial cells. Bronchial epithelial cells were cultured in the presence or absence of IL-17F and/or Th2 cytokines (IL-4 and IL-13) or various kinase inhibitors to analyze the expression of IL-11. Next, activation of mitogen- and stress-activated protein kinase (MSK) 1 by IL-17F was investigated. Moreover, the effect of short interfering RNAs (siRNAs) targeting MSK1 and cAMP response element binding protein (CREB) on IL-17F-induced IL-11 expression was investigated. IL-17F induced IL-11 expression, whereas the costimulation with IL-4 and IL-13 augmented this effect even further. MEK inhibitors PD-98059, U0126, and Raf1 kinase inhibitor I, significantly inhibited IL-11 production, whereas overexpression of a Raf1 dominant-negative mutant inhibited its expression. IL-17F clearly phosphorylated MSK1, whereas PD-98059 inhibited the phosphorylation of IL-17F-induced MSK1. Both MSK1 inhibitors Ro-31-8220 and H89 significantly blocked IL-11 expression. Moreover, transfection of the cells with siRNAs targeting MSK1 inhibited activation of CREB, and the siRNAs targeting MSK1 and CREB blocked expression of IL-11. These data suggest that IL-17F may be involved in airway inflammation and remodeling via the induction of IL-11, and RafI-MEK1/2-ERK1/2-MSK1-CREB is identified as a novel signaling pathway participating in this process. Therefore, the IL-17F/IL-11 axis may be a valuable therapeutic target for asthma.
AJP Lung Cellular and Molecular Physiology 03/2009; 296(5):L804-10. · 3.66 Impact Factor
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ABSTRACT: Lung parenchymal metastases are common manifestations; however, endobronchial metastasis is rare. We present herein a case of endobronchial metastasis from adrenocortical carcinoma. In the English language literature, this is the first case with such rare metastasis from adrenocortical carcinoma diagnosed antemortem. Although very rare, physicians should keep in mind the possibility of endobronchial metastasis in patients with a history of extrapulmonary malignancy including adrenocortical carcinoma.
Internal Medicine 02/2009; 48(13):1161-4. · 0.94 Impact Factor
