Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form


Amatya, Nilesh (2019) POST-TRANSCRIPTIONAL CONTROL OF IL-17 RECEPTOR-MEDIATED INFLAMMATION. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Download (5MB) | Preview


Interleukin-17A (commonly known as IL-17) is a pro-inflammatory cytokine critical in host
defense against microbial pathogens. However, dysregulated IL-17 receptor signaling drives
many autoimmune conditions including psoriasis, multiple sclerosis and autoimmune glomerulonephritis. Activation of inflammatory gene transcription through NF-κB is one of the most well-characterized IL-17 signaling pathways. However, IL-17 is consistently found to be a modest activator of transcription in experimental settings. Thus, the profound biological functions of IL-17 in vivo are often attributed to post-transcriptional control of IL-17 target gene expression, but the fundamental mechanisms remain largely underexplored. In this dissertation, I have focused on understanding the basic principles underlying IL-17-induced post-transcriptional regulation of inflammatory genes. Here, I describe two novel RNA-binding proteins (RBP) that promote IL-17-induced inflammation. In chapter 3, I have focused on
understanding how IL-17 promotes inflammation by regulating mRNA stability and mRNA translation through an RNA-binding protein called AT-rich interactive domain-containing protein 5A (Arid5a). Arid5a stabilizes mRNAs encoding IL-17-driven genes such as Il6, Cxcl1
and Cxcl5 by directly binding to their 3’UTR. Arid5a also enhances mRNA translation of key transcription factors such as C/EBPβ and IκBξ, which in turn facilitate transcription of IL-17 target genes. In chapter 4, I identified another RBP, which acts as an activator of IL-17 signaling. This RBP upregulates expression of
IL-17-dependent genes at least in part by triggering NF-κB. Mice deficient in this RBP are less
susceptible to IL-17-dependent autoimmune models such as experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune glomerulonephritis (EAGN).
Interestingly, this RBP does not affect Th17 differentiation in vivo or in vitro. Using radiation
chimeras, I found that this RBP functions dominantly in the non-hematopoietic compartment to induce kidney damage during EAGN. These results are consistent with a model in which this novel RBP positively regulates IL-17 mediated signaling rather than affecting Th17 cell
differentiation. Therefore, my dissertation research has deepened our understanding of how RBPs play essential roles in controlling IL-17 signaling post-transcriptionally. Understanding these mechanisms would be beneficial for designing oligonucleotides or small molecule inhibitors that can restrain RBP-mRNA interactions to dampen inflammation during autoimmune


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Amatya, Nileshnia25@pitt.edunia250000-0002-7942-1742
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorGaffen,
Committee ChairGaffen,
Committee MemberD'cruz,
Committee MemberKane,
Committee MemberSarkar,
Committee MemberO'sullivan,
Date: 3 January 2019
Date Type: Publication
Defense Date: 10 October 2018
Approval Date: 3 January 2019
Submission Date: 28 November 2018
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 178
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Interleukin-17, Arid5a, RNA-binding proteins, post-transcriptional gene regulation
Date Deposited: 03 Jan 2019 20:03
Last Modified: 03 Jan 2024 06:15


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item