α-MSH Modulates Local and Circulating Tumor Necrosis Factor-α in Experimental Brain Inflammation

Tumor necrosis factor (TNF-α) underlies pathological processes and functional disturbances in acute and chronic neurological disease and injury. The neuroimmunomodulatory peptide α-MSH modulates actions and production of proinflammatory cytokines including TNF-α, but there is no prior evidence that it alters TNF-α induced within the brain. To test for this potential influence of the peptide, TNF-α was induced centrally by local injection of bacterial lipopolysaccharide (LPS). α-MSH given once i.c.v. with LPS challenge, twice daily intraperitoneally (i.p.) for 5 d between central LPS injections, or both i.p. and centrally, inhibited production of TNF-α within brain tissue. Inhibition of TNF-α protein formation by α-MSH was confirmed by inhibition of TNF-α mRNA. Plasma TNF-α concentration was elevated markedly after central LPS, indicative of an augmented peripheral host response induced by the CNS signal. The increase was inhibited by α-MSH treatments, in relation to inhibition of central TNF-α. Presence within normal mouse brain of mRNA for the α-MSH receptor MC-1 suggests that the inhibitory effects of α-MSH on brain and plasma TNF-α might be mediated by this receptor subtype. The inhibitory effect of α-MSH on brain TNF-α did not depend on circulating factors because the effect also occurred in brain tissuein vitro. This indicates that α-MSH can act directly on brain cells to inhibit their production of TNF-α. If central TNF-α contributes to pathology in CNS disease and injury, and promotes inflammation in the periphery, agents that act on brain α-MSH receptors should decrease the pathological TNF-α reaction and promote tissue survival.

[1]  P. Holzer Proinflammatory and Antiinflammatory Peptides , 1998 .

[2]  J. M. Lipton,et al.  Anti-inflammatory actions of the neuroimmunomodulator α-MSH , 1997 .

[3]  J. M. Lipton,et al.  The neuropeptide α-MSH has specific receptors on neutrophils and reduces chemotaxis in vitro , 1996, Peptides.

[4]  J. M. Lipton,et al.  α‐MSH production, receptors, and influence on neopterin in a human monocyte/macrophage cell line , 1996 .

[5]  E. Hol,et al.  ACTH-related peptides: Receptors and signal transduction systems involved in their neurotrophic and neuroprotective actions , 1995, Peptides.

[6]  J. Wikberg,et al.  Expression of melanocortin 1 receptor in periaqueductal gray matter. , 1995, Neuroreport.

[7]  J. M. Lipton,et al.  Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[8]  S. Wesselingh,et al.  Unifying hypothesis for the pathogenesis of HIV-associated dementia complex, vacuolar myelopathy, and sensory neuropathy. , 1995, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[9]  P. Nisen,et al.  Modulation of expression of genes involved in the inflammatory response by lipopolysaccharide and temperature in cultured human astroglial cells. , 1995, Immunological investigations.

[10]  L. Mccawley,et al.  Cytokine elevations in infants with bacterial and aseptic meningitis. , 1995, The Journal of pediatrics.

[11]  K. Selmaj,et al.  Experimental autoimmune encephalomyelitis , 1995, Neurology.

[12]  D. Ferrari,et al.  Activation of microglial cells by β-amyloid protein and interferon-γ , 1995, Nature.

[13]  G. Fantuzzi,et al.  Independent down-regulation of central and peripheral tumor necrosis factor production as a result of lipopolysaccharide tolerance in mice , 1995, Infection and immunity.

[14]  J. Merrill,et al.  The mapping of HIV-1 gpl60 epitopes required for interleukin-1 and tumor necrosis factor a production in glial cells , 1995, Journal of Neuroimmunology.

[15]  L. Pulliam,et al.  The HIV envelope protein gp120 is toxic to human brain‐cell cultures through the induction of interleukin‐6 and tumor necrosis factor‐&agr; , 1995, AIDS.

[16]  J. M. Lipton,et al.  Antiinflammatory influences of alpha-MSH molecules: central neurogenic and peripheral actions , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[17]  J. M. Lipton,et al.  Central neurogenic antiinflammatory action of alpha-MSH: modulation of peripheral inflammation induced by cytokines and other mediators of inflammation. , 1994, Neuroendocrinology.

[18]  M. Cuzner,et al.  Cytokine mRNA expression in inflammatory multiple sclerosis lesions: detection by non-radioactive in situ hybridization. , 1993, Cytokine.

[19]  J. Crocker,et al.  Ependymal cells of the choroid plexus express tumour necrosis factor‐α 1 , 1993, Neuropathology and applied neurobiology.

[20]  P. Kragsbjerg,et al.  Tumor Necrosis Factor-α (TNFα) in Cerebrospinal Fluid from Patients with Meningitis of Different Etiologies: High Levels of TNFα Indicate Bacterial Meningitis , 1993 .

[21]  J. Merrill,et al.  Induction of interleukin-1 and tumor necrosis factor alpha in brain cultures by human immunodeficiency virus type 1 , 1992, Journal of virology.

[22]  J. M. Lipton,et al.  Central administration of the peptide α-MSH inhibits inflammation in the skin , 1991, Peptides.

[23]  J. M. Lipton,et al.  MODULATION OF INFLAMMATORY EFFECTS OF CYTOKINES BY THE NEUROPEPTIDE ALPHA -MSH , 1998 .

[24]  J. M. Lipton,et al.  The Protective Effects of α-Melanocyte Stimulating Hormone on Canine Brain Stem Ischemia. , 1997, Neurosurgery.

[25]  J. M. Lipton,et al.  The protective effects of α-melanocyte stimulating hormone on canine brain stem ischemia , 1997 .

[26]  C. Raine The Dale E. McFarlin memorial lecture: The immunology of the multiple sclerosis lesion , 1994, Annals of neurology.

[27]  B. Rowlands,et al.  The presence of tumour necrosis factor in CSF and plasma after severe head injury. , 1994, British journal of neurosurgery.

[28]  F. Barone,et al.  Cytokines, inflammation, and brain injury: role of tumor necrosis factor-alpha. , 1994, Cerebrovascular and brain metabolism reviews.

[29]  J. M. Lipton,et al.  Pyrogenic and Inflammatory Actions of Cytokines and Their Modulation by Neuropeptides: Techniques and Interpretations , 1993 .

[30]  M. Horsmanheimo,et al.  Lung biology in health and disease , 1977 .