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A decoy peptide derived from TIR domain of TIRAP inhibits TLR signaling pathway
- Alternative Title
- GUI XIANGAI
- Author(s)
- GUI, XIANGAI
- Alternative Author(s)
- GUI XIANGAI
- Advisor
- 최상돈
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2017-02
- Language
- eng
- Alternative Abstract
- ABSTRACT Toll-like receptors (TLRs) belong to the family of type I transmembrane proteins. These receptors are capable of recognizing specific parts of microbes and are able of activating different groups of signaling molecules. The activation of these receptors leads to a protective innate immune response against invading microbial and viral pathogens along with the production of inflammatory cytokines, chemokines, and type I interferons. However, an excessive TLRs-mediated immune response is associated with the onset and/or the aggravation of various inflammatory and auto-immune diseases. Thus, targeting TLRs or TLRs adaptor molecules offers a promising therapeutic approach for the inhibition of inflammation-related diseases. TIRAP (Toll/interleukin-1 receptor (TIR) domain containing adaptor protein) is an important adaptor molecule that is involved in TLR4 signaling spread. Herein, a TIRAP derived peptide, TIP1, has been assessed to hinder the TLR4-mediated signaling pathway. TIP1 inhibited lipopolysaccharide (LPS)-induced activation of NF-κB and MAPKs, and diminished the TLR4-mediated production of pro-inflammatory cytokines (i.e. IL-6 and TNF-α). It also reduced the expression levels of iNOS, COX2, and suppressed intracellular NO production, NO secretion and intracellular ROS generation. TIP1 also potently inhibited TLR3-mediated TNF-α and IFN-β secretion. Cell imaging by confocal microscopy, western blotting, and in vitro studies demonstrated that TIP1 preferentially inhibits TLR4, 3-mediated signaling and it also slightly hinders TLR2/1, 2/6, 7, 8, 9-mediated signaling. Finally, TIP1 diminished systemic cytokine responses (i.e. TNF-α, IL-12p40 and IL-6) elicited in vivo by LPS at 2 h challenge. Thus, TIP1 represents a novel inhibitory agent that majorly suppresses TLR4- and TLR3-mediated inflammatory response and blocks protein-protein interaction of the downstream mediators.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 3. Theses(Master)
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