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Effects of Klebsiella pneumoniae on Toll-Like Receptor-Dependent Endoplasmic Reticulum Stress-Related Signaling Pathways and Gene Expression and Promotes HLA-B27 Misfolding




Author(s)

Wen-Jen Cheng, Yu-Ling Wei, James Cheng-Chung Wei, Chia-Wei Lin, Hui-Yin Lu, Yu-Pu Hsia, Pei-Jane Tsai, Ying­Chun Lai, Yu-Liang Kuo and Ming-Shiou Jan

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DOI:10.17265/2328-2150/2016.12.003

Klebsiella has been considered as initiator of AS (ankylosing spondylitis) for nearly four decades. This study aimed to demonstrate that Klebsiella triggers ERS (endoplasmic reticulum stress) and HLA-B27 heavy chain misfolding. CA46 cells or splenocytes obtained from wild-type, MyD88^-/- or TLR9^-/- mice were stimulated with KP (Klebsiella pneumoniae) or its components including CPS (capsule polysaccharide), LPS (lipopolysaccharide), and KP gDNA (genomic deoxyribonucleic acid) respectively for 24 h and 48 h. The activation of ERS-related signaling was detected by Western blotting or RT-PCR, and the level of misfolded HLA-B27 was determined by non-reducing protein gel electrophoresis and Western blotting. The protein expression of BiP/Grp78 and calreticulin, the alternative splicing of XBP-1 mRNA (messenger ribonucleic acid), and the activation of caspase-12 and p38 were increased in a dose-dependent manner in HLA-B27-expressing CA46 cells after treatment with decapsulated KP. We also demonstrate that the ERS-inducing effects occur via the TLR (Toll-like receptor)/MyD88-dependent signaling pathway. Significantly, HLA-B27 misfolding was also detected in decapsulated KP-treated B27-expressing cells. These results suggest that the non-antigen-specific induction of ERS and B27 misfolding through TLR/MyD88 signaling might promote KP antigen-initiated autoreactive responses via the presentation of misfolded B27, and that small-molecules targeting TLRs might have potential as novel therapeutic agents for AS.

Klebsiella pneumoniae, endoplasmic reticulum stress, ankylosing spondylitis, Toll-like receptor 9, MyD88, HLA-B27 misfolding.

Cheng, W-J., et al. 2016. “Effects of Klebsiella pneumoniae on Toll-Like Receptor-Dependent Endoplasmic Reticulum Stress-Related Signaling Pathways and Gene Expression and Promotes HLA-B27 Misfolding.” Journal of Pharmacy and Pharmacology 4 (12): 667-678.