Allergy Asthma Immunol Res.  2015 May;7(3):256-264. 10.4168/aair.2015.7.3.256.

Antiallergic Function of KR62980, a Peroxisome Proliferator-Activated Receptor-gamma Agonist, in a Mouse Allergic Rhinitis Model

• Lee JE
• Zhang YL
• Han DH
• Kim DY
• Rhee CS

• KMID: 2260463
• DOI: http://doi.org/10.4168/aair.2015.7.3.256

Abstract

PURPOSE
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been shown to play an important role in the control of inflammatory responses acting on macrophages, mast cells, T cells and eosinophils. A novel PPAR-gamma ligand, KR62980 have been recently focused on due to the lower undesirable effects than other PPAR-gamma ligands such as rosiglitazone and pioglitazone. The present study was aimed to investigate the effects of KR62980 on nasal symptoms and immunopathological profiles in allergic nasal mucosa in murine allergic rhinitis model.
METHODS
BALB/c mice were sensitized and challenged intranasally with ovalbumin (OVA). KR62980 was administered intraperitoneally or orally 3 hours before each intranasal OVA challenge.
RESULTS
Administration of KR62980 significantly decreased the number of nasal rubbing, nasal sneezing, ova-specific IgE and total IgE in serum, secretion of Interleukin (IL)-4, IL-5, and IL-17 from the spleen and eosinophilic infiltration in the nasal mucosa. KR62980 decreased the expression of IL-4, IL-5 and IL-10 mRNAs in the nasal mucosal tissue, while, it elevated the level of IL-10 and IFN-gamma in splenocyte culture. KR62980 seemed to decrease IL-17 level in local and systemic level even though it did not reach to statistical significance. The anti-inflammatory effect was more definite when the KR62980 was administered intraorally than intraperitoneally.
CONCLUSIONS
A novel PPAR-gamma ligand, KR62980 can attenuate OVA-induced allergic inflammation in mice mainly through modulation of Th2 cytokines. This finding suggests that PPAR-gamma might have a role in the treatment of allergic rhinitis.

Keyword

Allergic rhinitis; PPAR gamma; T-Lymphocytes; regulatory; Interleukin-10; Interleukin-17

MeSH Terms

Animals
Cytokines
Eosinophils
Immunoglobulin E
Inflammation
Interleukin-10
Interleukin-17
Interleukin-4
Interleukin-5
Interleukins
Ligands
Macrophages
Mast Cells
Mice*
Mucous Membrane
Nasal Mucosa
Ovalbumin
Ovum
Peroxisomes*
PPAR gamma
Rhinitis*
RNA, Messenger
Sneezing
Spleen
T-Lymphocytes
Cytokines
Immunoglobulin E
Interleukin-10
Interleukin-17
Interleukin-4
Interleukin-5
Interleukins
Ligands
Ovalbumin
PPAR gamma
RNA, Messenger

Figure

• 

  Fig. 1 Protocol for allergen sensitization and challenge. Mice were sensitized on days 0, 7, and 14 by IP injection of OVA emulsified in alum hydroxide (OVA 25 ug + alum 2 mg)/300 µL/mouse. On days 22 through 29 after the initial sensitization, the mice were challenged with OVA (100 µg/20 µL/mouse) intranasally. KR62980 was administered intraperitoneally 4 times at 2-day intervals on days 22, 24, 26, and 28 in group C or by oral gavage on the same days in group D 3 hours before nasal challenge. D, day; PBS, phosphate-buffered saline; OVA, ovalbumin; IP, intraperitoneal administration; PO, per oral administration.

• 

  Fig. 2 Frequency of rubbing (A) and sneezing (B) for 10 minutes after the last ovalbumin (OVA) sensitization. The number of sneezing or nasal rubbing was significantly decreased in the KR62980-treated groups. *P<0.05. ns, not significant; OVA, ovalbumin; IP, intraperitoneal administration; PO, per oral administration.

• 

  Fig. 3 Effects of KR62980 in the mouse nasal tissue. (A) Representative sections of the nasal tissue are seen at a magnification of × 400 after hematoxylin and eosin staining. A marked reduction in the infiltration of inflammatory cells was observed in the KR62980-treated groups (groups C and D), similar to group A. (B) The number of eosinophils in the nasal septal mucosa. The number of eosinophils was significantly decreased in the KR62980-treated groups (groups C and D) (P=0.01). *P<0.05. ns, not significant; OVA, ovalbumin; IP, intraperitoneal administration; PO, per oral administration.

• 

  Fig. 4 Effects of KR62980 on levels of total IgE (A) and OVA-specific IgE (B) in the serum, and Th1/Th2 cytokines (C) in the spleen supernatant. KR62980 treatment reduced total IgE/OVA-specific IgE (serum) and IL-4/IL-5 (splenocyte) production significantly, while there were significant increments in IL-10 levels in the splenocyte culture supernatant. *P<0.05. ns, not significant; OVA, ovalbumin; IP, intraperitoneal administration; PO, per oral administration.

• 

  Fig. 5 Effects of KR62980 on the expressions of IL-4, IL-5, IL-10, and IFN-r mRNAs in the nasal mucosa. Oral or intraperitoneal administration of KR62980 (groups C and D) reduced the expressions of these mRNAs compared to group B. *P<0.05. ns, not significant; OVA, ovalbumin; IP, intraperitoneal administration; PO, per oral administration.

• 

  Fig. 6 Effects of KR62980 on the expression of IL-17 mRNA in the nasal tissue (A) and IL-17 in the splenocyte culture supernatant (B).The expression of IL-17 mRNA in the nasal tissue was reduced by administration of KR62980, while IL-17 expression in the splenocyte culture supernatant was not significantly reduced. ns, not significant; OVA, ovalbumin; IP, intraperitoneal administration; PO, per oral administration.

• 

  Fig. 7 Effects of KR62980 on the induction of the regulatory T-cell subgroups. After sensitization and challenge with OVA, a slight increase in CD4+CD25+FoxP3+ was observed, and the percentage of regulatory T cells seemed to further increase in the KR62980-treated group D. ns, not significant; OVA, ovalbumin; IP, intraperitoneal administration; PO, per oral administration.

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