Generation of expression constructs that secrete bioactive αMSH and their use in the treatment of experimental autoimmune encephalomyelitis

Yin, Peng; Luby, Thomas M.; Chen, Hongmin; Etemad-Moghadam, Bijan; Lee, D; Aziz, Nazneen; Ramstedt, Urban; Hedley, Mary Lynne

doi:10.1038/sj.gt.3301902

Cited by 26 publications

(27 citation statements)

References 38 publications

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“…Gene delivery of POMC minigene, such as ␣-MSH, has been applied to the treatment of inflammation in the central nervous system (Ichiyama et al, 1999), autoimmune encephalomyelitis (Yin et al, 2003), and liver failure (Wang et al, 2004). In the present study, the strategy of using the entire POMC precursor gene may be advantageous over the minigene approach in the following.…”

Section: Discussionmentioning

confidence: 98%

Gene Transfer of Pro-opiomelanocortin Prohormone Suppressed the Growth and Metastasis of Melanoma: Involvement of α-Melanocyte-Stimulating Hormone-Mediated Inhibition of the Nuclear Factor κB/Cyclooxygenase-2 Pathway

Liu

Liu²,

Lin³

et al. 2005

Mol Pharmacol

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Pro-opiomelanocortin (POMC) is a prohormone of various neuropeptides, including corticotropin, ␣-melanocyte-stimulating hormone (␣-MSH), and ␤-endorphin (␤-EP). POMC neuropeptides are potent inflammation inhibitors and immunosuppressants and may exert opposite influences during tumorigenesis. However, the role of POMC expression in carcinogenesis remains elusive. We evaluated the antineoplastic potential of POMC gene delivery in a syngenic B16-F10 melanoma model. Adenovirus-mediated POMC gene delivery in B16-F10 cells increased the release of POMC neuropeptides in cultured media, which differentially regulated the secretion of pro-and anti-inflammatory cytokines in lymphocytes. POMC gene transfer significantly reduced the anchorage-independent growth of melanoma cells. Moreover, pre-or post-treatment with POMC gene delivery effectively retarded the melanoma growth in mice. Intravenous injection of POMC-transduced B16-F10 cells resulted in reduced foci formation in lung by 60 to 70% of control. The reduced metastasis of POMC-transduced B16-F10 cells could be attributed to their attenuated migratory and adhesive capabilities. POMC gene delivery reduced the cyclooxygenase-2 (COX-2) expression and prostaglandin (PG) E 2 synthesis in melanoma cells and tumor tissues. In addition, application of NS-398, a selective COX-2 inhibitor, mimicked the antineoplastic functions of POMC gene transfer in melanoma. The POMC-mediated COX-2 down-regulation was correlated with its inhibition of nuclear factor B (NFB) activities. Exogenous supply of ␣-MSH inhibited NFB activities, whereas application of the ␣-MSH antagonist growth hormone-releasing peptide-6 (GHRP-6) abolished the POMC-induced inhibition of NFB activities and melanoma growth in mice. In summary, POMC gene delivery suppresses melanoma via ␣-MSH-induced inhibition of NFB/COX-2 pathway, thereby constituting a novel therapy for melanoma.POMC is a multifunctional polycistronic gene located on human chromosome 2p23.3. POMC is a 31 kDa prohormone that is processed into various neuropeptides, including corticotropin, melanotropins (␣-, ␤-, and ␥-MSH), lipotropins, and ␤-endorphin (␤-EP) (Solomon, 1999;Catania et al., 2004b). POMC peptides possess pleiotropic functions including pigmentation, adrenocortical function, regulation of energy stores, the immune system, and the central and peripheral

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Section: Discussionmentioning

confidence: 98%

Gene Transfer of Pro-opiomelanocortin Prohormone Suppressed the Growth and Metastasis of Melanoma: Involvement of α-Melanocyte-Stimulating Hormone-Mediated Inhibition of the Nuclear Factor κB/Cyclooxygenase-2 Pathway

Liu

Liu²,

Lin³

et al. 2005

Mol Pharmacol

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“…In addition, two other groups of researchers have attempted to use different forms of gene therapy to see if delivering α-MSH into the immune response of EAE will suppress the onset and subsequent pathology of EAE. One group engineered a naked DNA construct coding for the precleavage product of α-MSH (Yin et al, 2003). The plasmid was injected intra-muscularly at the time of MBP immunization to induce EAE, and then injected weekly after the mice were immunized.…”

Section: Discussionmentioning

confidence: 99%

The diminishment of experimental autoimmune encephalomyelitis (EAE) by neuropeptide alpha-melanocyte stimulating hormone (α-MSH) therapy

Taylor

Kitaichi

2008

Brain, Behavior, and Immunity

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The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) plays an important role in immune privilege by its suppression of inflammation, and its induction of regulatory T cells. This finding led us to test the possibility that we can use α-MSH to suppress autoimmune diseases, and promote re-establishment of immune tolerance to autoantigens. To test this possibility, SJL mice with experimental autoimmune encephalomyelitis (EAE) were injected with α-MSH at the first signs of paralysis. The α-MSH-treated mice in comparison with untreated EAE mice had a profound diminishment in the severity and tempo of EAE. The spleen cells in α-MSH-treated EAE produced TGF-β in response to PLP-antigen stimulation in contrast to untreated mice spleen cells that produced IFN-γ. When the α-MSH-treated EAE mice were reimmunized there was a delay of a week before the second episode of EAE. Although this delay maybe because of the induction of TGF-β-producing spleen cells by the α-MSH-treatment, it was not adequate to suppress IFN-γ-production by PLP-antigen stimulated spleen cells from untreated mice, nor able to suppress the eventual second episode of EAE. Therefore, the injection of α-MSH at the onset of paralysis is extremely effective in diminishing the severity and tempo of EAE, and the subsequent induction of potential PLP-specific Treg cells suggests that an α-MSH therapy could be attempted as part of a therapeutic regiment to impose immunoregulation and immunosuppression on an autoimmune disease of the central nervous system.

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“…51 In brief, the fusion construct that encoded the 13 amino acids of a-MSH inframe with a four-amino-acid extension (GGC AAG AAG CGG -ACTH 14 -17) as amidation sequence was cloned. This fusion construct was driven by a human cytomegalovirus promoter (pCMV-ACTH 1 -17).…”

Section: A-melanocyte-stimulating Hormone Expression Plasmid Preparationmentioning

confidence: 99%

Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation

et al. 2006

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Hepatic fibrosis represents a process of healing and scarring in response to chronic liver injury. a-Melanocyte-stimulating hormone (a-MSH) is a 13-amino-acid peptide with potent anti-inflammatory effects. We have previously demonstrated that a-MSH gene therapy protects against thioacetamide (TAA)-induced acute liver failure. Therefore, the aim of this study is to investigate whether a-MSH gene therapy possesses antihepatic fibrogenic effect. Liver fibrosis was induced by long-term TAA administration in mice. a-Melanocyte-stimulating hormone expression plasmid was delivered via electroporation after liver fibrosis was established. Our results showed that a-MSH gene therapy attenuated liver fibrosis in TAA-treated mice. Reverse transcription polymerase chain reaction revealed that a-MSH gene therapy attenuated the liver transforming growth factor-b1, collagen a1 and cell adhesion molecule mRNA upregulation. Following gene transfer, the expression of a-smooth muscle actin and cyclooxygenase-2 were both significantly attenuated. Further, a-MSH significantly increased matrix metalloproteinase (MMP), while tissue inhibitors of matrix metalloproteinase (TIMPs) were inactivated. In summary, a-MSH gene therapy reversed established liver fibrosis in mice and prevented the upregulated fibrogenic and pro-inflammatory gene responses after TAA administration. Its collagenolytic effect might be attributed to MMP and TIMP modulation. Hence, a-MSH gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use.

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Generation of expression constructs that secrete bioactive αMSH and their use in the treatment of experimental autoimmune encephalomyelitis

Cited by 26 publications

References 38 publications

Gene Transfer of Pro-opiomelanocortin Prohormone Suppressed the Growth and Metastasis of Melanoma: Involvement of α-Melanocyte-Stimulating Hormone-Mediated Inhibition of the Nuclear Factor κB/Cyclooxygenase-2 Pathway

Gene Transfer of Pro-opiomelanocortin Prohormone Suppressed the Growth and Metastasis of Melanoma: Involvement of α-Melanocyte-Stimulating Hormone-Mediated Inhibition of the Nuclear Factor κB/Cyclooxygenase-2 Pathway

The diminishment of experimental autoimmune encephalomyelitis (EAE) by neuropeptide alpha-melanocyte stimulating hormone (α-MSH) therapy

Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation

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