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CHARACTERIZATION OF BIOLOGICAL FUNCTION OF INTERACTION BETWEEN TLR4 AND PLIC-1

Biswas, Nabanita (2007) CHARACTERIZATION OF BIOLOGICAL FUNCTION OF INTERACTION BETWEEN TLR4 AND PLIC-1. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Toll-like receptors (TLRs) are key innate immune receptors that recognize non-self pathogens and trigger host responses. Activation of these receptors results in the release of antimicrobial peptides, inflammatory cytokines, and co stimulatory molecules that initiate adaptive immunity for infections with gram-negative bacteria, lipopolysaccharide is the main source of inflammation, and toll-like receptor 4 (TLR4) is crucial in mediating its effects. TLR4 is expressed on cardiomyocytes, macrophages, airway epithelia, endothelial, smooth-muscle cells and in small amounts in most other tissue. But, uncontrolled activation of TLR signaling molecules may cause auto immune diseases, sepsis, and tissue damage so the activation of TLR4 should be under control. Ubiquitin¨Cdependent receptor degradation as well as stabilization was recently suggested as a novel regulatory mechanism in controlling several TLR activations. We have recently found that an ubiquitin-like protein named protein linking integrin associated protein to cytoskeleton 1 (PLIC-1) interacts with the cytoplasmic domain of TLR4. The interaction between TLR4 and PLIC-1 was verified by western blot and immunoprecipitation. Further mapping of the interacting domain was done and we observed that the N terminal fragment of PLIC-1 is interacting with TLR4. PLIC-1 has been reported to stabilize proteins by interfering with proteosomal degradation. Consistent with this finding, we observed that over expression of PLIC-1 accumulated ubiquitinated TLR4. By flow cytometric analysis we observed that over expression of PLIC-1 is stabilizing TLR4. Reporter studies show that PLIC-1 inhibits the TRIF-dependent IFN-¦Â pathway. When endogenous PLIC-1 was knocked down by RNAi, the activation of TRIF-dependent IFN-¦Â luc was further increased. The same effect was observed in J774 mouse macrophages. Taken together our results suggest that PLIC-1 is a negative regulator of TLR pathway. This knowledge may be applied in immunotherapy as a means to modulate TLR activation in diseases such as septic shock, thus provides benefit for public health.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Biswas, Nabanitanab31@pitt.edu, nab1320@yahoo.comNAB31
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWang, Tianyitywang@pitt.eduTYWANG
Committee MemberHackam, Davidhackamd@upmc.edu
Committee MemberMartinson, Jeremyjmartins@pitt.eduJMARTINS
Date: 15 February 2007
Date Type: Completion
Defense Date: 15 December 2006
Approval Date: 15 February 2007
Submission Date: 8 December 2006
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: mutation
Other ID: http://etd.library.pitt.edu/ETD/available/etd-12082006-125251/, etd-12082006-125251
Date Deposited: 10 Nov 2011 20:09
Last Modified: 15 Nov 2016 13:53
URI: http://d-scholarship.pitt.edu/id/eprint/10202

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