JAK Inhibitors AG-490 and WHI-P154 Decrease IFN-<mml:math alttext="$\gamma$" id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>-Induced iNOS Expression and NO Production in Macrophages

Sareila, Outi; Korhonen, Riku; Kärpänniemi, Outi; Nieminen, Riina; Kankaanranta, Hannu; Moilanen, Eeva

doi:https://doi.org/10.1155/MI/2006/16161

Mediators of Inflammation

On this page

Abstract References Copyright Related Articles

Research Communication | Open Access

Volume 2006 | Article ID 016161 | https://doi.org/10.1155/MI/2006/16161

JAK Inhibitors AG-490 and WHI-P154 Decrease IFN-γ-Induced iNOS Expression and NO Production in Macrophages

Outi Sareila,¹Riku Korhonen,¹Outi Kärpänniemi,¹Riina Nieminen,¹Hannu Kankaanranta,¹and Eeva Moilanen¹

Received10 Jan 2006

Accepted28 Jan 2006

Published19 Mar 2006

Abstract

In inflammation, inducible nitric oxide synthase (iNOS) produces nitric oxide (NO), which modulates inflammatory processes. We investigated the effects of Janus kinase (JAK) inhibitors, AG-490 and WHI-P154, on iNOS expression and NO production in J774 murine macrophages stimulated with interferon-γ (IFN-γ). JAK inhibitors AG-490 and WHI-P154 decreased IFN-γ-induced nuclear levels of signal transducer and activator of transcription 1α (STAT1α). JAK inhibitors AG-490 and WHI-P154 decreased also iNOS protein and mRNA expression and NO production in a concentration-dependent manner. Neither of the JAK inhibitors affected the decay of iNOS mRNA when determined by actinomycin D assay. Our results suggest that the inhibition of JAK-STAT1-pathway by AG-490 or WHI-P154 leads to the attenuation of iNOS expression and NO production in IFN-γ-stimulated macrophages.

References

D A Geller and T R Billiar, “Molecular biology of nitric oxide synthases,” Cancer and Metastasis Reviews, vol. 17, no. 1, pp. 7–23, 1998.
View at: Google Scholar
H Kleinert, A Pautz, K Linker, and P M Schwarz, “Regulation of the expression of inducible nitric oxide synthase,” European Journal of Pharmacology, vol. 500, no. 1–3, pp. 255–266, 2004.
View at: Google Scholar
J MacMicking, Q W Xie, and C Nathan, “Nitric oxide and macrophage function,” Annual Review of Immunology, vol. 15, pp. 323–350, 1997.
View at: Google Scholar
R Korhonen, A Lahti, H Kankaanranta, and E Moilanen, “Nitric oxide production and signaling in inflammation,” Current Drug Targets. Inflammation and Allergy, vol. 4, no. 4, pp. 471–479, 2005.
View at: Google Scholar
E Moilanen, B J Whittle, and S Moncada, “Nitric oxide as a factor of inflammation,” in Inflammation: Basic Principles and Clinical Correlates, J I Gallin and R Snyderman, Eds., pp. 787–801, Lippincott Williams & Wilkins, Philadelphia, Pa, 1999.
View at: Google Scholar
S P Sanders, “Nitric oxide in asthma. Pathogenic, therapeutic, or diagnostic?” American Journal of Respiratory Cell and Molecular Biology, vol. 21, no. 2, pp. 147–149, 1999.
View at: Google Scholar
R J van't Hof and S H Ralston, “Nitric oxide and bone,” Immunology, vol. 103, no. 3, pp. 255–261, 2001.
View at: Google Scholar
P Vallance and J Leiper, “Blocking NO synthesis: how, where and why?” Nature Reviews. Drug Discovery, vol. 1, no. 12, pp. 939–950, 2002.
View at: Google Scholar
L C Platanias, “Mechanisms of type-I- and type-II-interferon-mediated signalling,” Nature Reviews. Immunology, vol. 5, no. 5, pp. 375–386, 2005.
View at: Google Scholar
A Lahti, U Jalonen, H Kankaanranta, and E Moilanen, “c-Jun NH2-terminal kinase inhibitor anthra(1,9-cd)pyrazol-6(2H)-one reduces inducible nitric-oxide synthase expression by destabilizing mRNA in activated macrophages,” Molecular Pharmacology, vol. 64, no. 2, pp. 308–315, 2003.
View at: Google Scholar
L C Green, D A Wagner, J Glogowski, P L Skipper, J S Wishnok, and S R Tannenbaum, “Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids,” Analytical Biochemistry, vol. 126, no. 1, pp. 131–138, 1982.
View at: Google Scholar
L B Ivashkiv and X Hu, “Signaling by STATs,” Arthritis Research & Therapy, vol. 6, no. 4, pp. 159–168, 2004.
View at: Google Scholar
W J Leonard and J J O'Shea, “Jaks and STATs: biological implications,” Annual Review of Immunology, vol. 16, pp. 293–322, 1998.
View at: Google Scholar
T Kisseleva, S Bhattacharya, J Braunstein, and C W Schindler, “Signaling through the JAK/STAT pathway, recent advances and future challenges,” Gene, vol. 285, no. 1-2, pp. 1–24, 2002.
View at: Google Scholar
L Gatto, C Berlato, V Poli et al., “Analysis of SOCS-3 promoter responses to interferon gamma,” The Journal of Biological Chemistry, vol. 279, no. 14, pp. 13746–13754, 2004.
View at: Google Scholar
J Blanchette, M Jaramillo, and M Olivier, “Signalling events involved in interferon-gamma-inducible macrophage nitric oxide generation,” Immunology, vol. 108, no. 4, pp. 513–522, 2003.
View at: Google Scholar
Q W Xie, Y Kashiwabara, and C Nathan, “Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase,” The Journal of Biological Chemistry, vol. 269, no. 7, pp. 4705–4708, 1994.
View at: Google Scholar
J Gao, D C Morrison, T J Parmely, S W Russell, and W J Murphy, “An interferon-gamma-activated site (GAS) is necessary for full expression of the mouse iNOS gene in response to interferon-gamma and lipopolysaccharide,” The Journal of Biological Chemistry, vol. 272, no. 2, pp. 1226–1230, 1997.
View at: Google Scholar
M A Meraz, J M White, K C Sheehan et al., “Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway,” Cell, vol. 84, no. 3, pp. 431–442, 1996.
View at: Google Scholar
L Martinez-Lostao, J Briones, I Forne et al., “Role of the STAT1 pathway in apoptosis induced by fludarabine and JAK kinase inhibitors in B-cell chronic lymphocytic leukemia,” Leukemia & Lymphoma, vol. 46, no. 3, pp. 435–442, 2005.
View at: Google Scholar
E A Sudbeck, X P Liu, R K Narla et al., “Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents,” Clinical Cancer Research, vol. 5, no. 6, pp. 1569–1582, 1999.
View at: Google Scholar
H Y Song, E S Jeon, J S Jung, and J H Kim, “Oncostatin M induces proliferation of human adipose tissue-derived mesenchymal stem cells,” The International Journal of Biochemistry & Cell Biology, vol. 37, no. 11, pp. 2357–2365, 2005.
View at: Google Scholar
H E Tibbles, A Vassilev, H Wendorf et al., “Role of a JAK3-dependent biochemical signaling pathway in platelet activation and aggregation,” The Journal of Biological Chemistry, vol. 276, no. 21, pp. 17815–17822, 2001.
View at: Google Scholar
R Korhonen, A Lahti, M Hamalainen, H Kankaanranta, and E Moilanen, “Dexamethasone inhibits inducible nitric-oxide synthase expression and nitric oxide production by destabilizing mRNA in lipopolysaccharide-treated macrophages,” Molecular Pharmacology, vol. 62, no. 3, pp. 698–704, 2002.
View at: Google Scholar

Copyright

Copyright © 2006 Outi Sareila et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation Order printed copies

Views

309

Downloads

855

Citations