Mechanisms of Allergy
TNF-α contributes to the development of allergic rhinitis in mice

https://doi.org/10.1067/mai.2003.1554Get rights and content

Abstract

Background: Allergic rhinitis is an inflammation involving TH2-type cytokine production, with pathologic eosinophil infiltration in the nasal mucosa. Although TNF-α is thought to be a pro-inflammatory cytokine, the relationship between TNF-α and allergic rhinitis has not been clarified. Objectives: The role of TNF-α in a murine model of ovalbumin (OVA)-sensitized allergic rhinitis was investigated by using mice deficient in the gene encoding TNF-α (TNF-α–/– mice). Methods: Both wild-type (TNF-α+/+) and TNF-α–/– mice were sensitized with OVA by means of intraperitoneal injection. They were then challenged with intranasal OVA, and various allergic responses were assessed. Results: The production of OVA-specific IgE in the serum (P < .05) and the frequency of sneezes (P < .05) and nasal rubs (P < .05) decreased significantly in TNF-α–/– mice after OVA sensitization compared with that in TNF-α+/+ mice (P < .05). The mRNA expression of IL-4, IL-10, and eotaxin in nasal mucosa in TNF-α–/– mice was also significantly suppressed compared with that in TNF-α+/+ mice after OVA sensitization (P < .05). Furthermore, the expression of both endothelial-leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1 mRNA in the nasal mucosa was significantly suppressed (P < .05), although intercellular adhesion molecule 1 mRNA expression did not decrease significantly in TNF-α–/– mice compared with that in TNF-α+/+ mice after OVA sensitization. In addition, the effect of TNF-α on endothelial-leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1 expression by means of Western blot analysis was compatible with the mRNA results. Pathologically, eosinophil infiltration in nasal mucosa was significantly restricted in TNF-α–/– mice compared with in TNF-α+/+ mice after OVA sensitization (P < .05). Conclusion: TNF-α is necessary for antigen-specific IgE production and for the induction of TH2-type cytokines and chemokines. Furthermore, TNF-α might be important for the expression of adhesion molecules to recruit eosinophils to the allergic inflammatory site. We conclude that the lack of TNF-α inhibited the development of allergic rhinitis. (J Allergy Clin Immunol 2003;112:134-40.)

Section snippets

Mice

The C57BL/6 strain of TNF-α–/– mice were generated in our laboratory, as described previously.13 BALB/c mice were obtained from Japan SLC Inc (Hamamatsu, Japan). TNF-α–/– male mice (20-25 g) and wild-type (TNF-α+/+) male mice (20-25 g) were obtained from homozygous inbreeding in the F2 generation (C57BL/6 x BALB/c) because BALB/c mice are thought to be high responders with respect to ovalbumin (OVA), whereas C57BL/6 mice are low responders.14

Sensitization of mice

TNF-α+/+ and TNF-α–/– mice, hereafter referred to as

Appearance of nasal symptoms

Sneezes and nasal rubs were observed for 10 minutes after the last intranasal challenge. As shown in Fig 1, the frequency of sneezes and nasal rubs was significantly lower in TNF-α–/– (OVA) mice than in TNF-α+/+ (OVA) mice (P < .05).

. Appearance of nasal symptoms: A, sneezes; B, nasal rubs. Values are means ± SEM of 7 to 18 animals for each group. *P < .05, significantly different from TNF-α+/+ (control) or TNF-α–/– (control) values. #P < .05, significantly different from TNF-α+/+ (OVA) values.

Serum total IgE and OVA-specific IgE

Discussion

The present study clarifies the relationship between TNF-α and antigen-specific IgE production and the necessity of TNF-α for the induction of TH2-type cytokines and chemokines in allergic rhinitis.

It is widely accepted that IL-4 is involved in both IgE production and antigen-specific IgE production,16, 17 and IL-10 has a positive role in the induction of the antigen-specific IgE response.18 It has been recently reported that TNF-α enhances allergic sensitization. Pretreatment with TNF-α before

Acknowledgements

We appreciate the technical assistance of S. Fujigaki, N. Furuta, and H. Ohashi.

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    Reprint requests: Kuniaki Saito, PhD, LNT, NIMH, Building 10 Room 3D42, MSC 1262, 10 Center Dr, Bethesda, MD 20892-1262.

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