Tags

Type your tag names separated by a space and hit enter

A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia.
Neuropharmacology 2004; 47(2):243-52N

Abstract

Excessive proinflammatory cytokine and NO production by activated microglia play a role in neurodegenerative disorders. In this study, we found that a new compound KL-1037 suppressed LPS-induced NO release/inducible nitric oxide synthase expression in BV2 mouse microglial cells. In addition, KL-1037 prominently diminished LPS-induced production of pro-inflammatory cytokines such as TNF-alpha, IL-1 beta and IL-6, while it increased anti-inflammatory IL-10 and TGF-beta 1 production. By RNase protection assay and RT-PCR, we showed that KL-1037 regulated iNOS and cytokines at transcriptional or post-transcriptional level. Further analysis of molecular mechanisms revealed that KL-1037 prominently increased intracellular cAMP levels and potentiated LPS-induced pCREB expression. However, LPS-induced MAP kinase or NF-kappa B activities were slightly or little changed by KL-1037. Treatment with cAMP antagonist or IL-10 neutralizing antibody completely reversed upregulation of IL-10 and partially repression of TNF-alpha or NO induced by KL-1037. These data suggest that microglial inactivation by KL-1037 is at least in part due to activation of PKA pathway and/or upregulation of IL-10. Thus, repressing proinflammatory cytokines and iNOS gene expression in activated microglia by KL-1037 may provide potential therapeutic strategies for various neurodegenerative diseases including ischemic cerebral disease.

Authors+Show Affiliations

Department of Pharmacology, Ewha Institute of Neuroscience and Medical Research Center, Ewha Womans University School of Medicine, Seoul, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15223303

Citation

Kim, Won-Ki, et al. "A New Anti-inflammatory Agent KL-1037 Represses Proinflammatory Cytokine and Inducible Nitric Oxide Synthase (iNOS) Gene Expression in Activated Microglia." Neuropharmacology, vol. 47, no. 2, 2004, pp. 243-52.
Kim WK, Jang PG, Woo MS, et al. A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia. Neuropharmacology. 2004;47(2):243-52.
Kim, W. K., Jang, P. G., Woo, M. S., Han, I. O., Piao, H. Z., Lee, K., ... Kim, H. S. (2004). A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia. Neuropharmacology, 47(2), pp. 243-52.
Kim WK, et al. A New Anti-inflammatory Agent KL-1037 Represses Proinflammatory Cytokine and Inducible Nitric Oxide Synthase (iNOS) Gene Expression in Activated Microglia. Neuropharmacology. 2004;47(2):243-52. PubMed PMID: 15223303.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia. AU - Kim,Won-Ki, AU - Jang,Pil-Geum, AU - Woo,Moon-Sook, AU - Han,In-Oc, AU - Piao,Hua Zi, AU - Lee,Keumho, AU - Lee,Heesoon, AU - Joh,Tong H, AU - Kim,Hee-Sun, PY - 2003/09/26/received PY - 2004/02/27/revised PY - 2004/03/29/accepted PY - 2004/6/30/pubmed PY - 2004/9/29/medline PY - 2004/6/30/entrez SP - 243 EP - 52 JF - Neuropharmacology JO - Neuropharmacology VL - 47 IS - 2 N2 - Excessive proinflammatory cytokine and NO production by activated microglia play a role in neurodegenerative disorders. In this study, we found that a new compound KL-1037 suppressed LPS-induced NO release/inducible nitric oxide synthase expression in BV2 mouse microglial cells. In addition, KL-1037 prominently diminished LPS-induced production of pro-inflammatory cytokines such as TNF-alpha, IL-1 beta and IL-6, while it increased anti-inflammatory IL-10 and TGF-beta 1 production. By RNase protection assay and RT-PCR, we showed that KL-1037 regulated iNOS and cytokines at transcriptional or post-transcriptional level. Further analysis of molecular mechanisms revealed that KL-1037 prominently increased intracellular cAMP levels and potentiated LPS-induced pCREB expression. However, LPS-induced MAP kinase or NF-kappa B activities were slightly or little changed by KL-1037. Treatment with cAMP antagonist or IL-10 neutralizing antibody completely reversed upregulation of IL-10 and partially repression of TNF-alpha or NO induced by KL-1037. These data suggest that microglial inactivation by KL-1037 is at least in part due to activation of PKA pathway and/or upregulation of IL-10. Thus, repressing proinflammatory cytokines and iNOS gene expression in activated microglia by KL-1037 may provide potential therapeutic strategies for various neurodegenerative diseases including ischemic cerebral disease. SN - 0028-3908 UR - https://www.unboundmedicine.com/medline/citation/15223303/A_new_anti_inflammatory_agent_KL_1037_represses_proinflammatory_cytokine_and_inducible_nitric_oxide_synthase__iNOS__gene_expression_in_activated_microglia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028390804000942 DB - PRIME DP - Unbound Medicine ER -