Histamine H1 receptor-stimulated interleukin 8 and granulocyte macrophage colony-stimulating factor production by bronchial epithelial cells requires extracellular signal-regulated kinase signaling via protein kinase C.
BACKGROUND
Histamine stimulates the release of several cytokines, such as interleukin (IL)-8 and granulocyte macrophage colony-stimulating factor, from bronchial epithelial cells. However, the functional individual histamine receptor subtype and intracellular signaling in bronchial epithelial cells are poorly defined.


METHODS
Using human primary epithelial cells and the NCI-H292 cell line, we examined the expression of histamine receptor subtypes and histamine-induced second messenger. We also evaluated the involvements of mitogen-activated protein kinase, protein kinase C (PKC) and epidermal growth factor receptor in cytokine expression caused by histamine.


RESULTS
Histamine H1 receptor (H1R) was the only subtype expressed in both types of cells. Histamine elevated intracellular calcium ion without affecting cAMP levels. Histamine induced the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Histamine also phosphorylated PKC and myristoylated alanine-rich C kinase substrate. Ro-31-8220, a PKC inhibitor, and PD98059, a mitogen-activated protein/ERK kinase inhibitor, suppressed the histamine-induced ERK activation and the production of granulocyte macrophage colony-stimulating factor and IL-8. On the contrary, histamine had no effect on the phosphorylation of epidermal growth factor receptor, and its specific inhibitor AG1478 failed to inhibit the histamine-induced ERK activation. Olopatadine, an H1 antagonist, completely blocked the histamine-related responses, whereas H2 and H3 antagonists did not. Histamine also augmented the IL-8 production caused by IL-4 or tumor necrosis factor-alpha.


CONCLUSIONS
The H1R-PKC-ERK pathway may play crucial roles in eliciting cytokine production from bronchial epithelial cells stimulated by histamine, leading to airway inflammation.
Matsubara
Masahiro
M
Department of Pharmacology and Molecular Biology, Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan. masahiro.matsubara@kyowa.co.jp
Ohmori
Kenji
K
Hasegawa
Kazuhide
K
D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006632:Histamine / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D009093:Mucus / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism; D015398:Signal Transduction
D016207:Cytokines; D016209:Interleukin-8; D011969:Receptors, Histamine H1; D006632:Histamine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases