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Inducible Nitric Oxide Synthase Can Be Induced in the Absence of Active Nuclear Factor-B in Rat Mesangial Cells

Involvement of the JanusKinase 2 Signaling Pathway

Second Department of Internal Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

Correspondence to Dr. Yoshio Terada, Second Department of Internal Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyou-ku, Tokyo 113-8519, Japan. Phone: 81-3-5803-5216; Fax: 81-3-5803-0132; E-mail: yterada.med2{at}med.tmd.ac.jp

Abstract. The contribution of nuclear factor-B (NF-B) and interferon- (IFN-) signaling to nitric oxide generation is not completely understood. The effect of NF-B release and its inhibition on nitrite production and the involvement of Janus kinase 2 (JAK2) in inducible nitric oxide synthase (iNOS) induction were investigated. The following assays were performed. (1) Nitrite produced by rat mesangial cells in primary culture was measured in incubations with tumor necrosis factor- (TNF-) or lipopolysaccharide (LPS), with or without IFN-. Cells were stimulated with TNF- or LPS plus IFN- in the presence of NF-B inhibitors, herbimycin A (HerA), or the more specific JAK2 inhibitor AG490. (2) Immunoblotting was performed against the p65 and p50 subunits of NF-B and iNOS. (3) Electrophoretic mobility shift assays were performed against NF-B in the presence of NF-B inhibitors or AG490. (4) iNOS promoter activity was measured in the presence of AG490 or JAK2 antisense oligonucleotides. TNF- or LPS alone did not induce nitrite production, but with IFN- these compounds did induce nitrite production. Pyrrolidine dithiocarbamate (PDTC), N-acetyl-L-cysteine, dexamethasone (Dex), HerA, and AG490 partially inhibited LPS/IFN-- or TNF-/IFN--induced nitrite production. p65 was inhibited by the three NF-B inhibitors described above, whereas p50 was not. PDTC and Dex completely inhibited the p65/p50 heterodimer, but HerA and AG490 had little effect on p65/p50. AG490 and JAK2 antisense oligonucleotides suppressed iNOS promoter activity. It can be concluded that (1) iNOS can be induced without active NF-B; (2) Dex, acetylsalicylic acid, and PDTC inhibit only p65; and (3) JAK2 is involved in iNOS induction, and the contribution of JAK2 to nitrite production is greater than that of NF-B.

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