Antiproliferative effects of NKH477, a forskolin derivative, on cytokine profile in rat lung allografts

Shinji Nakashima, Masayuki Morikawa, Kanshi Komatsu, Akihiro Matsuura, Noriyuki Sato, Tomio Abe

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Objective: NKH477 was recently identified as a water-soluble forskolin derivative and was reported to prolong survival of murine cardiac allografts. However, the mechanism of the efficacy is not clear in vivo. The aim of this study was to investigate the immunosuppressive effects of NKH477 on acute lung allograft rejection in the rat model and its mechanism of action in vivo. Methods: Left lungs were transplanted orthotopically from Brown-Norway donors to Lewis recipients. Recipient rats were untreated or treated daily with different doses of NKH477. Grafts were excised on Day 3 or Day 5 to determine histopathological rejection and expressions of interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-γ by enzyme-linked immunosorbent assay. The cytokine expression at Day 3 or Day 5 was also evaluated in recipient spleens by immunohistochemistry. Furthermore, mesenteric lymph node cells from recipients at Day 5 were cultured alone or stimulated with donor antigens for 72 hours to determine cell proliferation by means of thymidine incorporation. Results: NKH477 significantly extended allograft survival time in a dose-dependent manner and reduced histopathological rejection. Treatment with NKH477 inhibited IFN-γ and IL-10 expression, whereas expression of these cytokines were markedly upregulated in the untreated allografts. Expression of IL-2 and IL-10 also increased in the spleen of untreated allorecipients. NKH477 suppressed expression of both cytokines in the spleen. In addition, lymphocyte proliferation was inhibited in NKH477-treated recipients as compared with untreated recipients. Conclusion: These results suggest that NKH477 exerts an antiproliferative effect on lymphocytes in vivo with an altered cytokine profile in rat recipients of lung allografts.

Original languageEnglish
Pages (from-to)462-469
Number of pages8
JournalJournal of Heart and Lung Transplantation
Volume24
Issue number4
DOIs
Publication statusPublished - 01-01-2005

Fingerprint

Colforsin
Allografts
Cytokines
Lung
Interleukin-10
Spleen
Interferons
Interleukin-2
Lymphocytes
Norway
Immunosuppressive Agents
Interleukin-4
Thymidine
Lymph Nodes
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Cell Proliferation
Transplants
Antigens
Water

All Science Journal Classification (ASJC) codes

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

Cite this

Nakashima, Shinji ; Morikawa, Masayuki ; Komatsu, Kanshi ; Matsuura, Akihiro ; Sato, Noriyuki ; Abe, Tomio. / Antiproliferative effects of NKH477, a forskolin derivative, on cytokine profile in rat lung allografts. In: Journal of Heart and Lung Transplantation. 2005 ; Vol. 24, No. 4. pp. 462-469.
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Antiproliferative effects of NKH477, a forskolin derivative, on cytokine profile in rat lung allografts. / Nakashima, Shinji; Morikawa, Masayuki; Komatsu, Kanshi; Matsuura, Akihiro; Sato, Noriyuki; Abe, Tomio.

In: Journal of Heart and Lung Transplantation, Vol. 24, No. 4, 01.01.2005, p. 462-469.

Research output: Contribution to journalArticle

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T1 - Antiproliferative effects of NKH477, a forskolin derivative, on cytokine profile in rat lung allografts

AU - Nakashima, Shinji

AU - Morikawa, Masayuki

AU - Komatsu, Kanshi

AU - Matsuura, Akihiro

AU - Sato, Noriyuki

AU - Abe, Tomio

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N2 - Objective: NKH477 was recently identified as a water-soluble forskolin derivative and was reported to prolong survival of murine cardiac allografts. However, the mechanism of the efficacy is not clear in vivo. The aim of this study was to investigate the immunosuppressive effects of NKH477 on acute lung allograft rejection in the rat model and its mechanism of action in vivo. Methods: Left lungs were transplanted orthotopically from Brown-Norway donors to Lewis recipients. Recipient rats were untreated or treated daily with different doses of NKH477. Grafts were excised on Day 3 or Day 5 to determine histopathological rejection and expressions of interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-γ by enzyme-linked immunosorbent assay. The cytokine expression at Day 3 or Day 5 was also evaluated in recipient spleens by immunohistochemistry. Furthermore, mesenteric lymph node cells from recipients at Day 5 were cultured alone or stimulated with donor antigens for 72 hours to determine cell proliferation by means of thymidine incorporation. Results: NKH477 significantly extended allograft survival time in a dose-dependent manner and reduced histopathological rejection. Treatment with NKH477 inhibited IFN-γ and IL-10 expression, whereas expression of these cytokines were markedly upregulated in the untreated allografts. Expression of IL-2 and IL-10 also increased in the spleen of untreated allorecipients. NKH477 suppressed expression of both cytokines in the spleen. In addition, lymphocyte proliferation was inhibited in NKH477-treated recipients as compared with untreated recipients. Conclusion: These results suggest that NKH477 exerts an antiproliferative effect on lymphocytes in vivo with an altered cytokine profile in rat recipients of lung allografts.

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