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Molecular mechanisms of TLR4- and No...

University of California, Los Angeles.

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Molecular mechanisms of TLR4- and Nod2-mediated innate immune responses.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Molecular mechanisms of TLR4- and Nod2-mediated innate immune responses./
Author:	Chang, Elmer Yeong-Shin.
Description:	93 p.
Notes:	Adviser: Genhong Cheng.
Contained By:	Dissertation Abstracts International68-09B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3280925
ISBN:	9780549234050

Molecular mechanisms of TLR4- and Nod2-mediated innate immune responses.
Chang, Elmer Yeong-Shin.

Molecular mechanisms of TLR4- and Nod2-mediated innate immune responses. - 93 p.

Adviser: Genhong Cheng.

Thesis (Ph.D.)--University of California, Los Angeles, 2007.

Pattern recognition receptors such as Toll-like receptor 4 (TLR4) and nucleotide oligomerization domain 2 (Nod2), expressed by innate immune cells translate the recognition of pathogen-associated molecular patterns (PAMPs) into rapid upregulation of pro-inflammatory cytokines that serve to combat infection. However, excess production of these cytokines is harmful to the host. To avoid this, negative regulators such as IL-10 are also produced in response to PAMPs to feedback inhibit the pro-inflammatory response. This delicate balance between pro- and anti-inflammatory responses is especially crucial for maintaining gut homeostasis. Defects in either pro- or anti-inflammatory responses such as Nod2 mutation or IL-10 deficiency have been linked to Crohn's disease (CD), a chronic inflammatory condition that affects the gastrointestinal tract. However, the molecular events responsible for PAMP-induced IL-10 upregulation and Nod2-mediated innate immunity remain to be elucidated. Therefore, in this dissertation, we investigated the signaling pathways involved in lipopolysaccharide (LPS)-induced IL-10 production and Nod2-mediated pro-inflammatory response in an attempt to better understand the pathogenesis of CD. In the first part of the dissertation, we provide evidence that the production of and signaling by type I interferon (IFN) is required for LPS-induced IL-10 upregulation in bone marrow-derived macrophages (BMDMs). Moreover, we establish that type I IFN per se can induce IL-10 production and subsequent Stat3 phosphorylation. Finally, we demonstrate that defects in type I IFN production and signaling result in LPS-mediated superinduction of pro-inflammatory cytokines. Our findings suggest a novel anti-inflammatory role for the type I IFN production and signaling pathway in regulating LPS responses in BMDMs. In the second part of the dissertation, we show that N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP), a subunit of peptidoglycan (PGN) recently found to be a Nod2-specific ligand, upregulates pro-inflammatory genes and cytokine in wild type but not receptor interacting protein 2 (Rip2)-deficient BMDMs. Likewise, MDP-induced activation of mitogen-activated protein kinases (MAPK) and nuclear factor-kappaB (NF-kappaB) observed in Rip2+1+ BMDMs is abrogated in Rip2-/- cells. Our results indicate that Nod2-mediated pro-inflammatory response is Rip2-dependent. We believe that characterizing the signaling pathways involved in the maintenance of gut homeostasis would help us design targeted molecular therapies for CD in the future.

ISBN: 9780549234050Subjects--Topical Terms:

1017719
Biology, Molecular.

Molecular mechanisms of TLR4- and Nod2-mediated innate immune responses.
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245 1 0 $a Molecular mechanisms of TLR4- and Nod2-mediated innate immune responses.
300 $a 93 p.
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500 $a Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 5731.
502 $a Thesis (Ph.D.)--University of California, Los Angeles, 2007.
520 $a Pattern recognition receptors such as Toll-like receptor 4 (TLR4) and nucleotide oligomerization domain 2 (Nod2), expressed by innate immune cells translate the recognition of pathogen-associated molecular patterns (PAMPs) into rapid upregulation of pro-inflammatory cytokines that serve to combat infection. However, excess production of these cytokines is harmful to the host. To avoid this, negative regulators such as IL-10 are also produced in response to PAMPs to feedback inhibit the pro-inflammatory response. This delicate balance between pro- and anti-inflammatory responses is especially crucial for maintaining gut homeostasis. Defects in either pro- or anti-inflammatory responses such as Nod2 mutation or IL-10 deficiency have been linked to Crohn's disease (CD), a chronic inflammatory condition that affects the gastrointestinal tract. However, the molecular events responsible for PAMP-induced IL-10 upregulation and Nod2-mediated innate immunity remain to be elucidated. Therefore, in this dissertation, we investigated the signaling pathways involved in lipopolysaccharide (LPS)-induced IL-10 production and Nod2-mediated pro-inflammatory response in an attempt to better understand the pathogenesis of CD. In the first part of the dissertation, we provide evidence that the production of and signaling by type I interferon (IFN) is required for LPS-induced IL-10 upregulation in bone marrow-derived macrophages (BMDMs). Moreover, we establish that type I IFN per se can induce IL-10 production and subsequent Stat3 phosphorylation. Finally, we demonstrate that defects in type I IFN production and signaling result in LPS-mediated superinduction of pro-inflammatory cytokines. Our findings suggest a novel anti-inflammatory role for the type I IFN production and signaling pathway in regulating LPS responses in BMDMs. In the second part of the dissertation, we show that N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP), a subunit of peptidoglycan (PGN) recently found to be a Nod2-specific ligand, upregulates pro-inflammatory genes and cytokine in wild type but not receptor interacting protein 2 (Rip2)-deficient BMDMs. Likewise, MDP-induced activation of mitogen-activated protein kinases (MAPK) and nuclear factor-kappaB (NF-kappaB) observed in Rip2+1+ BMDMs is abrogated in Rip2-/- cells. Our results indicate that Nod2-mediated pro-inflammatory response is Rip2-dependent. We believe that characterizing the signaling pathways involved in the maintenance of gut homeostasis would help us design targeted molecular therapies for CD in the future.
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