Anti-inflammatory actions of the neuroimmunomodulator α-MSH

Lipton, James M.; Catania, Anna

doi:10.1016/s0167-5699(97)01009-8

Cited by 346 publications

(259 citation statements)

References 30 publications

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“…The peptide is safe when given in large and consistent doses to animals or humans. 26,27,29 However, it is very unstable in vivo and therapeutic use would require daily administration. 26,27,29 Researchers have been developing aMSH analogs, such as [Cys4, Cys10]-aMSH 33 and [Nle4,D-Phe7]-aMSH 34 , to increase activity and stability relative to native aMSH.…”

Section: Discussionmentioning

confidence: 99%

“…22,23 The antiinflammatory activity of aMSH is due in part to inhibition of IkB degradation, 24,25 an effect that prevents the transcription factor nuclear factor kB (NF-kB) from entering the nucleus. NF-kB is required for the production of several pro-inflammatory factors, such as IL-1 and TNF-a 11,12,14,[26][27][28] , and has been shown to have a role in the pathogenesis of many inflammatory/autoimmune diseases. 25 The ability of aMSH to inhibit NF-kB translocation makes it an interesting target for therapeutic intervention.…”

mentioning

confidence: 99%

“…In fact, aMSH and its analogs have shown therapeutic activity in many animal disease models [11][12][13][14] such as inflammatory bowel disease, 26 arthritis 29 and hepatitis. 27 However, the inherent instability of the peptide does not make it suitable for use as a therapeutic agent in humans. 30 In an effort to recognize the potential of aMSH as a drug for the treatment of disease, we have applied a DNA approach and have generated two DNA expression constructs that secrete bioactive peptides with aMSH activity.…”

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confidence: 99%

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

et al. 2003

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a Melanocyte-stimulating hormone (aMSH) is a 13 amino acid peptide with potent anti-inflammatory effects. We created two DNA expression constructs (miniPOMC and pACTH1-17) that encode bioactive versions of the aMSH peptide, and tested these constructs for therapeutic effects in experimental autoimmune encephalomyelitis (EAE). Each construct contained the sequences for aMSH, as well as the sequences that are involved in the secretion and processing of the POMC gene with the assumption that these sequences would promote processing and release of the encoded aMSH peptide. The differences between the two constructs lie at the C-terminal end where amino acids necessary for amidation of aMSH were included in only the pACTH1-17 construct. These two constructs were tested in vitro in bioassays, and in vivo in a mouse model of EAE. The results show that although bioactive peptides are secreted from cells transfected with either construct, there appears to be a significant therapeutic effect only with the pACTH1-17 construct which contains the extra C-terminal amino acids. The data suggest that it is possible to engineer DNA expression vectors encoding small secreted peptides such as aMSH, and that similar type constructs may be useful as therapeutics for the treatment of inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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

et al. 2003

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“…a-Melanocyte-simulating hormone also has potent antipyretic and anti-inflammatory responses, inhibiting acute and chronic inflammation in a number of tissues (Lipton and Catania, 1997), including for example ultraviolet (UV) irradiation . Our group has showed that a-MSH can inhibit tumour necrosis factor-a (TNF-a)-induced upregulation of intercellular adhesion molecule-1 (ICAM-1) in human melanocytes and melanoma cells (Hedley et al, 1998b;Morandini et al, 1998) and reduce interactions between cytokine-stimulated melanoma cells and T lymphocytes .…”

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confidence: 99%

Anti-inflammatory and anti-invasive effects of α-melanocyte-stimulating hormone in human melanoma cells

et al. 2003

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a-Melanocyte stimulating hormone (a-MSH) is known to have pleiotrophic functions including pigmentary, anti-inflammatory, antipyretic and immunoregulatory roles in the mammalian body. It is also reported to influence melanoma invasion with levels of a-, b-and g-MSH correlated clinically with malignant melanoma development, but other studies suggest a-MSH acts to retard invasion. In the present study, we investigated the action of a-MSH on three human melanoma cell lines (HBL, A375-SM and C8161) differing in metastatic potential. a-melanocyte-simulating hormone reduced invasion through fibronectin and also through a human reconstructed skin composite model for the HBL line, and inhibited proinflammatory cytokine-stimulated activation of the NF-kB transcription factor. However, A375-SM and C8161 cells did not respond to a-MSH. Immunofluorescent microscopy and Western blotting identified melanocortin-1 receptor (MC-1R) expression for all three lines and MC-2R on HBL and A375-SM lines. Receptor binding identified a similar affinity for a-MSH for all three lines with the highest number of binding sites on HBL cells. Only the HBL melanoma line demonstrated a detectable cyclic adenosine monophosphate (cAMP) response to a-MSH, although all three lines responded to acute a-MSH addition ( þ (À)-N 6 -(2-phenylisopropyl)-adenosine (PIA)) with an elevation in intracellular calcium. The nonresponsive lines displayed MC-1R polymorphisms (C8161, Arg (wt) 151/Cys 151; A375-SM, homozygous Cys 151), whereas the HBL line was wild type. Stable transfection of the C8161 line with wild-type MC-1R produced cells whose invasion was significantly inhibited by a-MSH. From this data, we conclude that a-MSH can reduce melanoma cell invasion and protect cells against proinflammatory cytokine attack in cells with the wild-type receptor (HBL).

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“…16 a-Melanocyte-stimulating hormone (a-MSH) is a neuroimmunopeptide that plays a crucial role in the regulation of immune and inflammatory reactions. 17,[19][20][21] Studies suggest that a-MSH promotes the restoration of injured nerves and the spinal cord. 18 Research also suggests that a-MSH may inhibit the production and activity of proinflammatory cytokines, while enhancing the secretion of anti-inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

Prevention and treatment of experimental autoimmune encephalomyelitis with recombinant adeno-associated virus-mediated α-melanocyte-stimulating hormone-transduced PLP139-151-specific T cells

et al. 2006

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The aim of this study was to investigate the immunomodulatory effects and mechanism of action of alpha-melanocytestimulating hormone (a-MSH) gene modified proteolipid protein (PLP) 139-151-specific T cells (T PLP-a-MSH ) in the SJL mouse model of experimental autoimmune encephalomyelitis (EAE). PLP139-151-specific T cells (T PLP cells) were transduced with a recombinant adeno-associated virus 2 (rAAV2) encoding a-MSH. After activation with PLP139-151 in vitro, T PLP-a-MSH cells secreted high levels of a-MSH and also demonstrated an altered Th1-like cytokine pattern as well as a high frequency of CD4 + CD25 + Treg cells. Transfer studies showed that T PLP-a-MSH cells could suppress the induction of adoptive transfer EAE. More importantly, our studies demonstrated that T PLP-a-MSH cells had preventive and therapeutic effect on active relapse-remitting EAE (REAE) in an antigen-inducible manner. Suppression of REAE by T PLP-a-MSH cells was associated with a general reduction of inflammatory central nervous system (CNS) infiltrates, a pronounced decrease in Th1 cytokines and chemokines expression and an increase in Th2 cytokines. These data strongly suggested that local delivery of a-MSH by rAAV2-mediated a-MSH-transduced PLP139-151-specific T cells (T PLP-a-MSH ) would be a desirable new approach to the treatment of autoimmune disease in the CNS.

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Anti-inflammatory actions of the neuroimmunomodulator α-MSH

Cited by 346 publications

References 30 publications

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

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

Anti-inflammatory and anti-invasive effects of α-melanocyte-stimulating hormone in human melanoma cells

Prevention and treatment of experimental autoimmune encephalomyelitis with recombinant adeno-associated virus-mediated α-melanocyte-stimulating hormone-transduced PLP139-151-specific T cells

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