Functions of the Galanin Peptide Familiy in Inflammation

Inflammation is initiated during the process of innate immunity as a first step to combat possible pathogenic assaults to the human body. If left unchecked, inflammation can be deleterious to the host. Therefore, identifying the endogenous factors that control this aspect of host defence is a key goal in the field of immunology. The first barriers to external noxae and microbial organisms are the skin and mucous membranes. In these organs, various peptides produced by immune cells and skin cells exert potent anti-inflammatory functions. These peptides include calcitonin gene-related peptide, alpha-melanocyte stimulating hormone, pituitary adenylate cyclase- activating peptide, substance P, vasoactive intestinal peptide, norepinephrine, and galanin, released by cutaneous nerves or resident and infiltrating immune cells. Furthermore, systemic neuromediators and cutaneous nerves can influence a number of target cells within the skin and mucous membranes. The galanin peptide family consists of the `parental` peptide galanin; galanin-message associated peptide (GMAP), which derives from the same peptide precursor gene product as galanin; galanin-like peptide (GALP), encoded by a different gene; and the recently discovered peptide, alarin, a splice variant of the GALP mRNA. The galanin receptor family currently comprises three members, GalR1, GalR2 and GalR3, which are all G-protein-coupled receptors. Our recent data demonstrate that the peptides galanin, GALP and alarin exhibit anti-oedema activity in the skin. However, the precise modes of action of these peptides during inflammation remain unclear. We hypothesize that the galanin peptide family acts at different levels during inflammation, that the function is mediated by different receptors, and finally that the influence of galanin peptides on inflammation is not restricted to the skin. We propose to elucidate further functions and sites of action of the galanin peptides in inflammation and to elucidate the receptors involved. This will include analysis of the effects of galanin peptides on inflammatory cytokine production in both epithelial cells and immune cells such as neutrophils. To investigate possible systemic regulatory effects of these peptides, an animal model of sepsis will be analysed. Finally, analysis of the peptide receptors involved in these processes will provide targets for future therapeutic interventions. For the galanin family of peptides, a multi-component fail-safe system regulating inflammation can be envisioned in which some components of the galanin system are redundant, which is a common phenomenon in the evolution of physiological adaptations and body defence mechanisms. The studies in this proposal will clarify these regulatory circuits.

Inflammation is initiated during the process of innate immunity as a first step to combat possible pathogenic assaults to the human body. If left unchecked, inflammation can be deleterious to the host. Therefore, identifying the endogenous factors that control this aspect of host defence is a key goal in the field of immunology. The first barriers to external noxae and microbial organisms are the skin and mucous membranes. In these organs, various peptides produced by immune cells and skin cells exert potent anti-inflammatory functions. These peptides include calcitonin gene-related peptide, alpha-melanocyte stimulating hormone, pituitary adenylate cyclase-activating peptide, substance P, vasoactive intestinal peptide, norepinephrine, and galanin, released by cutaneous nerves or resident and infiltrating immune cells. Furthermore, systemic neuromediators and cutaneous nerves can influence a number of target cells within the skin and mucous membranes. The galanin peptide family consists of the "parental" peptide galanin; galanin-message associated peptide (GMAP), which derives from the same peptide precursor gene product as galanin; galanin-like peptide (GALP), encoded by a different gene; and the recently discovered peptide, alarin, a splice variant of the GALP mRNA. The galanin receptor family currently comprises three members, GalR1, GalR2 and GalR3, which are all G-protein-coupled receptors. Our recent data demonstrate that the peptides galanin, GALP and alarin exhibit anti-oedema activity in the skin. However, the precise modes of action of these peptides during inflammation remain unclear. We hypothesize that the galanin peptide family acts at different levels during inflammation, that the function is mediated by different receptors, and finally that the influence of galanin peptides on inflammation is not restricted to the skin. We propose to elucidate further functions and sites of action of the galanin peptides in inflammation and to elucidate the receptors involved. This will include analysis of the effects of galanin peptides on inflammatory cytokine production in both epithelial cells and immune cells such as neutrophils. To investigate possible systemic regulatory effects of these peptides, an animal model of sepsis will be analysed. Finally, analysis of the peptide receptors involved in these processes will provide targets for future therapeutic interventions. For the galanin family of peptides, a multi-component fail-safe system regulating inflammation can be envisioned in which some components of the galanin system are redundant, which is a common phenomenon in the evolution of physiological adaptations and body defence mechanisms. The studies in this proposal will clarify these regulatory circuits.