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

Int Arch Allergy Immunol. 2006;139(4):279-93. doi: 10.1159/000091599. Epub 2006 Feb 17.


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.

MeSH terms

  • Bronchi / cytology
  • Bronchi / metabolism*
  • Cytokines / biosynthesis
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis*
  • Histamine / physiology
  • Humans
  • Interleukin-8 / biosynthesis*
  • Mucus / metabolism
  • Protein Kinase C / metabolism*
  • Receptors, Histamine H1 / metabolism*
  • Respiratory Mucosa / metabolism
  • Signal Transduction*


  • Cytokines
  • Interleukin-8
  • Receptors, Histamine H1
  • Histamine
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Protein Kinase C
  • Extracellular Signal-Regulated MAP Kinases