The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Increase of NADPH-diaphorase Expression in Hypothalamus of Stat4 Knockout Mice

  • Published : 2009.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Signal transducer and activator of transcription 4 (STAT4), a STAT family member, mediates interleukin 12 (IL12) signal transduction. IL12 is known to be related to calorie-restricted status. In the central nervous system, IL12 also enhances the production of nitric oxide (NO), which regulates food intake. In this study, the expression of neuronal NO synthase (Nos1), which is also related to food intake, was investigated in the hypothalamic areas of Stat4 knockout (KO) mice using nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry, a marker for neurons expressing Nos1 enzyme. Western blots were also performed to evaluate Nos1 and Fos expression. Wild-type Balb/c (WT group, n=10 male) and Stat4 KO mice (Stat4 KO group, n=8 male) were used. The body weight and daily food intake in the WT group were $22.4{\pm}0.3$ and 4.4 g per day, while those in the Stat4 KO group were $18.7{\pm}0.4$ and 1.8 g per day, respectively. Stat4 mice had lower body weight and food intake than Balb/c mice. Optical intensities of NADPH-d-positive neurons in the paraventricular nucleus (PVN) and lateral hypothalamic area (LHA) of the Stat4 KO group were significantly higher than those of the WT group. Western blotting analysis revealed that the hypothalamic Nos1 and Fos expression of the Stat4 KO group was up-regulated, compared to that in the WT group. These results suggest that Stat4 may be related to the regulation of food intake and expression of Nosl in the hypothalamus.

Keywords

References

  1. Bredt DS. Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic Res 31: 577−596, 1999 https://doi.org/10.1080/10715769900301161
  2. Copeland NG, Gilbert DJ, Schindler C, Zhong Z, Wen Z, Darnell JE Jr, Mui AL, Miyajima A, Quelle FW, Ihle JN, Jenkins NA. Distribution of the mammalian Stat gene family in mouse chromosomes. Genomics 29: 225−228, 1995 https://doi.org/10.1006/geno.1995.1235
  3. Darnell JE Jr. STATs and gene regulation. Science 277: 1630−1635, 1997 https://doi.org/10.1126/science.277.5332.1630
  4. Darnell JE Jr, Kerr IM, Stark GM. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264: 1415−1421, 1994 https://doi.org/10.1126/science.8197455
  5. Dawson TM, Dawson VL, Snyder SH. A novel neuronal messenger molecule in brain: the free radical, nitric oxide. Ann Neurol 32: 297−311, 1992 https://doi.org/10.1002/ana.410320302
  6. Fenton JI, Nunez NP, Yakar S, Perkins SN, Hord NG, Hursting SD. Diet-induced adiposity alters the serum profile of inflammation in C57BL/6N mice as measured by antibody array. Diabetes Obes Metab 11: 343−354, 2009 https://doi.org/10.1111/j.1463-1326.2008.00974.x
  7. Frucht DM, Aringer M, Galon J, Danning C, Brown M, Fan S, Centola M, Wu CY, Yamada N, El Gabalawy H, O'Shea JJ. Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation. J Immunol 164: 4659−4664, 2000 https://doi.org/10.4049/jimmunol.164.9.4659
  8. Hoey T, Zhang S, Schmidt N, Yu Q, Ramchandani S, Xu X, Naeger LK, Sun YL, Kaplan MH. Distinct requirements for the naturally occurring splice forms Stat4alpha and Stat4beta in IL-12 responses. EMBO J 22: 4237−4248, 2003 https://doi.org/10.1093/emboj/cdg393
  9. Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382: 174−177, 1996 https://doi.org/10.1038/382174a0
  10. Kataoka TR, Komazawa N, Morii E, Oboki K, Nakano T. Involvement of connective tissue-type mast cells in Th1 immune responses via Stat4 expression. Blood 105: 1016−1020, 2005 https://doi.org/10.1182/blood-2004-07-2811
  11. Kim MJ, Kim Y, Choe BK, Kim SA, Lee HJ, Kim JW, Huh Y, Kim C, Chung JH. Differential expression of nicotinamide adenine dinucleotide phosphate-diaphorase in hypothalamic areas of obese Zucker rats. Neurosci Lett 292: 60−62, 2000 https://doi.org/10.1016/S0304-3940(00)01428-2
  12. Min SS. Effects of nos inhibitors on arthritis and arthritic pain in rats. Korean J Physiol Pharmacol 11: 253−257, 2007
  13. Moncada S. The 1991 Ulf von Euler Lecture. The L-arginine: nitric oxide pathway. Acta Physiol Scand 145: 201−227, 1992 https://doi.org/10.1111/j.1748-1716.1992.tb09359.x
  14. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109−142, 1991
  15. Morley JE, Flood JF. Competitive antagonism of nitric oxide synthase causes weight loss in mice. Life Sci 51: 1285−1289, 1992 https://doi.org/10.1016/0024-3205(92)90018-K
  16. Morley JE, Flood JF. Effect of competitive antagonism of NO synthase on weight and food intake in obese and diabetic mice. Am J Physiol 266: R164−168, 1994
  17. Morley JE, Flood JF. Evidence that nitric oxide modulates food intake in mice. Life Sci 49: 707−711, 1991 https://doi.org/10.1016/0024-3205(91)90102-H
  18. Morley JE, Mattammal MB. Nitric oxide synthase levels in obese Zucker rats. Neurosci Lett 209: 137−139, 1996 https://doi.org/10.1016/0304-3940(96)12622-7
  19. Raman K, Kaplan MH, Hogaboam CM, Berlin A, Lukacs NW. STAT4 signal pathways regulate inflammation and airway physiology changes in allergic airway inflammation locally via alteration of chemokines. J Immunol 170: 3859−3865, 2003
  20. Reiss CS, Komatsu T, Barna M, Bi Z. Interleukin-12 promotes enhanced recovery from viral infection of neurons in the central nervous system. Ann NY Acad Sci 795: 257−265, 1996 https://doi.org/10.1111/j.1749-6632.1996.tb52675.x
  21. Scherer-Singler U, Vincent SR, Kimura H, McGeer EG. Demonstration of a unique population of neurons with NADPH-diaphorase histochemistry. J Neurosci Methods 9: 229−234, 1983 https://doi.org/10.1016/0165-0270(83)90085-7
  22. Squadrito F, Calapai G, Altavilla D, Cucinotta D, Zingarelli B, Campo GM, Arcoraci V, Sautebin L, Mazzaglia G, Caputi AP. Food deprivation increases brain nitric oxide synthase and depresses brain serotonin levels in rats. Neuropharmacology 33: 83−86, 1994 https://doi.org/10.1016/0028-3908(94)90100-7
  23. Squadrito F, Calapai G, Cucinotta D, Altavilla D, Zingarelli B, Ioculano M, Urna G, Sardella A, Campo GM, Caputi AP. Anorectic activity of NG-nitro-L-arginine, an inhibitor of brain nitric oxide synthase, in obese Zucker rats. Eur J Pharmacol 230: 125−128, 1993 https://doi.org/10.1016/0014-2999(93)90422-E
  24. Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, Sangster MY, Vignali DA, Doherty PC, Grosveld GC, Ihle JN. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382: 171−174, 1996 https://doi.org/10.1038/382171a0
  25. Yang EK. Role of angiotensin II and nitric oxide in the rat paraventricular nucleus. Korean J Physiol Pharmacol 5: 41−46, 2001

Cited by

  1. Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome vol.21, pp.10, 2013, https://doi.org/10.1038/ejhg.2013.1
  2. Modulating Neuroinflammation to Treat Neuropsychiatric Disorders vol.2017, pp.None, 2009, https://doi.org/10.1155/2017/5071786