Universität zu Köln

Lu, Huayi, Lu, Qingxian, Gaddipati, Subhash ORCID: 0000-0002-5323-5466, Kasetti, Ramesh Babu, Wang, Wei, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Kaplan, Henry J. and Li, Qiutang (2014). IKK2 Inhibition Attenuates Laser-Induced Choroidal Neovascularization. PLoS One, 9 (1). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Choroidal neovascularization (CNV) is aberrant angiogenesis associated with exudative age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Inflammation has been suggested as a risk factor for AMD. The IKK2/NF-kappa B pathway plays a key role in the inflammatory response through regulation of the transcription of cytokines, chemokines, growth factors and angiogenic factors. We investigated the functional role of IKK2 in development of the laser-induced CNV using either Ikk2 conditional knockout mice or an IKK2 inhibitor. The retinal neuronal tissue and RPE deletion of IKK2 was generated by breeding Ikk2(-/flox) mice with Nestin-Cre mice. Deletion of Ikk2 in the retina caused no obvious defect in retinal development or function, but resulted in a significant reduction in laser-induced CNV. In addition, intravitreal or retrobulbar injection of an IKK2 specific chemical inhibitor, TPCA-1, also showed similar inhibition of CNV. Furthermore, in vitro inhibition of IKK2 in ARPE-19 cells significantly reduced heat shock-induced expression of NFKBIA, IL1B, CCL2, VEGFA, PDGFA, HIF1A, and MMP-2, suggesting that IKK2 may regulate multiple molecular pathways involved in laser-induced CNV. The in vivo laser-induced expression of VEGFA, and HIF1A in RPE and choroidal tissue was also blocked by TPCA-1 treatment. Thus, IKK2/NF-kappa B signaling appears responsible for production of pro-inflammatory and pro-angiogenic factors in laser-induced CNV, suggesting that this intracellular pathway may serve as an important therapeutic target for aberrant angiogenesis in exudative AMD.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lu, Huayi UNSPECIFIED UNSPECIFIED UNSPECIFIED Lu, Qingxian UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaddipati, Subhash UNSPECIFIED orcid.org/0000-0002-5323-5466 UNSPECIFIED Kasetti, Ramesh Babu UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Wei UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Kaplan, Henry J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Qiutang UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-448200
DOI:	10.1371/journal.pone.0087530
Journal or Publication Title:	PLoS One
Volume:	9
Number:	1
Date:	2014
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; ENDOTHELIAL GROWTH-FACTOR; PIGMENT EPITHELIAL-CELLS; ALPHA-INDUCED APOPTOSIS; NECROSIS-FACTOR-ALPHA; MACULAR DEGENERATION; CANCER-CELLS; TRANSCRIPTIONAL REGULATION; INCREASED EXPRESSION; MOUSE MODEL Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/44820