Abstract
Here we have characterized perthamide C, a cyclopeptide from a Solomon Lithistid sponge Theonella swinhoei, which displays an anti-inflammatory/immunomodulatory activity. The study has been performed using the carragenan-induced mouse paw edema that displays an early (0–6 h) and a late phase (24–96 h). Perthamide C significantly inhibits neutrophils infiltration in tissue both in the early and late phases. This effect was coupled to a reduced expression of the endothelial nitric oxide synthase (eNOS) in the early phase while cyclooxygenase-1 and 2 (COX-1, COX-2), and inducible NOS (iNOS) expression were unaffected. In the late phase perthamide C reduced expression of both NOS isoforms without affecting COXs expression. This peculiar selectivity toward the two enzymes deputed to produce NO lead us to investigate on a possible action of perthamide C on lymphocytes infiltration and activation. We found that perthamide C inhibited the proliferation of peripheral lymphocytes, and that this effect was secondary to its metabolic activation in vivo. Indeed, in vitro perthamide C did not inhibit proliferation as opposite to its metabolite perthamide H.In conclusion, perthamide C selectively interferes with NO generation triggered by either eNOS or iNOS without affecting either COX-1 or COX-2. This in turn leads to modulation of the inflammatory response through a reduction of vascular permeability, neutrophil infiltration as well as lymphocyte proliferation.
Highlights
Within marine invertebrates, sponges have developed a highly complex immune system associated to the capacity to produce efficiently secondary metabolites as a defence mechanism
We evaluated if perthamide C administration was able to modify the expression levels of the constitutive enzymes endothelial nitric oxide synthase (eNOS) and COX-1 as well as of their respective inducible isoforms, inducible NOS (iNOS) and COX-2
During the early phase of edema both eNOS and COX-1 were expressed in total extracts obtained from saline- and l-carrageenan-injected paw homogenates (Figure 2A and B)
Summary
Sponges have developed a highly complex immune system associated to the capacity to produce efficiently secondary metabolites as a defence mechanism. Acute inflammatory response is characterized by an increase in vascular permeability and cellular infiltration leading to oedema formation as a result of extravasation of fluid and proteins, and accumulation of leukocytes at the inflammatory site. Following these changes, many other mechanisms are activated, contributing to the amplification of the inflammatory response and tissue damage, leading to the development of a more complex ‘scenario’ e.g. the chronic inflammatory reaction. Since perthamide C given systemically resulted active at very low dose e.g 0.3 mg/kg ip we have investigated in details the mechanism of this powerful anti-inflammatory activity
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