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IL‐1beta Loss Contributes to Reduced Toxicity of the TRIF‐biased TLR4 agonist Monophosphate Lipid A
Author(s) -
Embry Chelsea Anne,
Ganhapudhi Siva,
Desta Dereje,
Mitchell Thomas
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.976.1
Subject(s) - trif , tlr4 , agonist , inflammation , in vivo , chemistry , lipopolysaccharide , in vitro , microbiology and biotechnology , signal transduction , pharmacology , biochemistry , receptor , endocrinology , biology , immunology , toll like receptor , innate immune system
Monophosphate Lipid A (MPLA) is a TRIF‐biased TLR4 agonist that retains the immuno‐stimulatory properties of its parent molecule lipopolysaccharide (LPS) while displaying 0.1–1% as much toxicity. We previously determined that TRIF‐biased signaling downstream of TLR4 activation by MPLA is responsible for loss of IL‐1beta maturation activity (C.A. Embry et al. Science Signaling 2011). While this mechanism was fully elucidate in vitro, the role of IL‐1beta in mediating differential inflammatory processes in vivo between the two TLR4 agonists, MPLA and LPS, has yet to be determined. In this study, IL‐1RI knock‐out mice (that are unable to induce inflammation in response to IL‐1beta) were compared to wild type in their ability to induce a pro‐inflammatory response after challenge with either MPLA or LPS. Serum and tissue samples from treated mice were analyzed for levels of IL‐RI/MyD88‐dependent factors at 1hr and 6hrs. Results suggest that strong IL‐1beta production induced by LPS can account for most of the differential activation of MyD88‐dependent inflammatory factors compared to MPLA at later time points in vivo. These results indicate that MPLA's TRIF‐biased TLR4 activation results in loss of factors that potentiate inflammation and toxicity.