OK-432 Administration Inhibits Murine Allergic Rhinitis at the Induction Phase, through the Macrophage Activation with TLR2 Signaling Pathway

Abstract

OK-432, a preparation of a low-virulence strain (Su) of Streptococcus pyogenes (Group A) killed by a penicillin and lyophilized, is a stiff inducer of Th1 cytokines, and exerts anti-cancer effects in tumor-bearing mice. OK-432 has been reported to consist of many bacterial components, such as peptidoglycan, M-protein, etc. However, it is yet to be ascertained which bacterial component induces T helper 1 (Th1) responses. For the last decade, Toll-like receptor (TLR) family proteins are well elucidated to play a role in recognizing bacterial components and inducing interleukin (IL)-12 from macrophages. Above all, peptidoglycan seems to be the agonist of TLR2 rather than the obverse. In our present study, the role of TLR2 for the recognition of OK-432 by macrophages and the effects of OK-432 are examined on murine allergic rhinitis model. Interestingly, results show IL-12 production by macrophages derived from TLR2 knock-out (ko) mice was significantly decreased, in comparison with that of macrophages derived from wild-type mice. Moreover, in TLR2 ko mice, no regulatory effect of OK-432 was observed on an allergic rhinitis model. These data indicate that TLR2 signaling is involved in regulating OK-432-induced anti-T helper 2 (Th2) immunity, and may offer a new prophylactic and therapeutic approach using OK-432 to downregulate allergic disorders, such as allergic rhinitis.

Toll-Like Receptor Agonists as Adjuvants for Allergen Immunotherapy

“…While some studies report enhancement of a Th2 allergic response, the majority favour a reduction of Th2 cytokines, cellular infiltrates in BAL fluid and upregulation of Th1 cytokine production and Treg proliferation. Future work and direction would ideally see the development of a suitable candidate for administration in humans, and it is possible that TLR2 agonists currently used therapeutically such as OK-432 for cancer, may be viable treatments for AR and asthma ( 78 ). A summary of TLR2/6 and TLR2/1 effects on allergic inflammation can be found in Figure 4 .…”

Total RNA and genomic DNA of Lactobacillus gasseri OLL2809 induce interleukin-12 production in the mouse macrophage cell line J774.1 via toll-like receptors 7 and 9

“…Lipopolysaccharide (LPS), a ligand of gram-negative bacteria for cell-surface-expressed TLR4, stimulates IL-12 production without being phagocytosed [ 11 ]. On the other hand, several gram-positive bacterial cell wall components such as peptidoglycan, a ligand for cell-surface expressed TLR2, are also involved in the induction of IL-12 production from macrophages [ 21 , 22 ]. To clarify whether stimulation of IL-12 production occurs without phagocytosis via cell-surface expressed PRRs or after phagocytosis followed by recognition of the immunostimulatory component of L. gasseri OLL2809 by intracellular PRRs, IL-12 production assay was performed after inhibition of phagocytosis using CyD.…”

Nasal Administration of Lipopolysaccharide Exacerbates Allergic Rhinitis through Th2 Cytokine Production from Mast Cells

“…TLR4 is reported to be expressed in the nasal epithelial cells of mice [13] or humans [14]. Neutrophil inflammation occurs when TLR2 agonist is administered to the nose of mice [15], but intranasal administration of LPS does not cause nasal inflammation (Supplementary Figure S1). LPS causes neutrophil inflammation in the lungs when administered intratracheally [16].…”