Allergy Asthma Immunol Res.  2014 Nov;6(6):567-572. 10.4168/aair.2014.6.6.567.

Histamine Promotes the Release of Interleukin-6 via the H1R/p38 and NF-kappaB Pathways in Nasal Fibroblasts

• Park IH
• Um JY
• Cho JS
• Lee SH
• Lee SH
• Lee HM

• KMID: 2260180
• DOI: http://doi.org/10.4168/aair.2014.6.6.567

Abstract

PURPOSE
Based on the close relationship between histamine and interleukin 6 (IL-6), we hypothesized that histamine may regulate the production of cytokines, such as IL-6, during allergic inflammation. Here, we examined the role of histamine in IL-6 production and histamine receptor activity in nasal fibroblasts, along with the mechanisms underlying these effects.
METHODS
Experiments were performed using nasal fibroblasts from 8 normal patients. RT-PCR was used to identify the major histamine receptors expressed in nasal fibroblasts. Fibroblasts were then treated with histamine with or without histamine-receptor antagonists, and monitored for IL-6 production using an ELISA. Four potential downstream signaling molecules, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-kappaB, were evaluated by Western blot, and a luciferase reporter assay.
RESULTS
Elevated expression was seen for all histamine receptors, with IL-6 protein levels increasing significantly following histamine stimulation. Among the histamine-receptor specific antagonists, only the H1R antagonist significantly decreased IL-6 production in histamine-stimulated nasal fibroblasts. Histamine increased the expression level of phosphorylated p38 (pp38), pERK, and pJNK, as well as NF-kappaB induction. The H1R antagonist actively suppressed pp38 and NF-kappaB expression in histamine-induced nasal fibroblasts, but not pERK and pJNK. The p38 inhibitor strongly attenuated IL-6 production in histamine-stimulated nasal fibroblasts.
CONCLUSIONS
The data presented here suggest that antihistamines may be involved in the regulation of cytokines, such as IL-6, due to the role of histamine as an inflammatory mediator in nasal fibroblasts.

Keyword

Nose; fibroblast; histamine; IL-6; allergic rhinitis

MeSH Terms

Blotting, Western
Cytokines
Enzyme-Linked Immunosorbent Assay
Fibroblasts*
Histamine Antagonists
Histamine*
Humans
Inflammation
Interleukin-6*
JNK Mitogen-Activated Protein Kinases
Luciferases
NF-kappa B*
Nose
Phosphotransferases
Receptors, Histamine
Cytokines
Histamine
Histamine Antagonists
Interleukin-6
JNK Mitogen-Activated Protein Kinases
Luciferases
NF-kappa B
Phosphotransferases
Receptors, Histamine

Figure

• 

  Fig. 1 Messenger RNA levels of histamine receptors in nasal fibroblasts. Gene expression levels were determined by RT-PCR.

• 

  Fig. 2 ELISA of the effects of histamine on IL-6 production in nasal fibroblasts. Values are expressed as the means±SE of independent experiments. *P<0.05 vs control, **P<0.01 vs control.

• 

  Fig. 3 The effect of histamine receptor antagonists on IL-6 production in histamine-stimulated nasal fibroblasts was determined by ELISA. Nasal fibroblasts were pretreated with antagonists for H1R (H1RA, fexofenadine), H2R (H2RA, ranitidine), H3R (H3RA clobenpropit), and H4R (H4RA, JNJ7777120) for 2 hours prior to histamine (100 µM) stimulation. Values are expressed as the means±SE of independent experiments. *P<0.05 vs control. †P<0.05 vs histamine alone.

• 

  Fig. 4 A dose-response analysis of H1R antagonist fexofenadine on IL-6 production was determined by ELISA. Values are expressed as the means±SE of independent experiments. *P<0.05 vs control.

• 

  Fig. 5 The effect of H1R antagonist fexofenadine on the phosphorylation of mitogen-activated protein kinases (ERK, p38, JNK) was evaluated by Western blotting (representative of independent experiments). U0126, ERK inhibitor; SB203580, p38 inhibitor; SP600125, JNK inhibitor.

• 

  Fig. 6 Effect of p38 inhibition on IL-6 production in histamine-stimulated nasal fibroblasts. Values are expressed as the means±S.E. *P<0.05 vs control. †P<0.05 vs histamine alone.

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  Fig. 7 Effects of an H1R antagonist on NF-κB expression (A) and IL-6 production (B) in histamine-stimulated nasal fibroblasts. Values are expressed as the means±SE. *P<0.05 vs control. †P<0.05 vs histamine alone.

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