Distinct chemotactic and angiogenic activities of peptides derived from Kaposi's sarcoma virus encoded chemokines.
The vMIPs are chemokine-like proteins expressed by the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) during the lytic phase of viral infection. vMIP-I activates CCR8, a chemokine receptor expressed by Th2 lymphocytes and cultured monocytes. vMIP-II is an agonist for CCR3, a receptor expressed by eosinophils, and an antagonist for several other chemokine receptors. Both are highly angiogenic in the chick chorio-allantoic membrane. We designed and tested three 26-mer peptides, derived from vMIP-I (pK-I), from vMIP-II (pK-II) and from the control MIP-1alpha (pM), spanning key residues of chemokines. pK-I, pK-II and pM all were able to activate a strong chemotactic response in monocytes, higher than parental vMIP-I and II. This corresponded to induction of calcium fluxes in these cells, typical of chemokines. Interestingly, pK-II and pM were also active on PMN neutrophils. In vivo studies (matrigel sponge and rabbit cornea models) showed that pK-I retains the strong angiogenic potential exerted by vMIP-I, while pK-II and pM induced an inflammatory response, probably mediated by PMN recruitment. Our observations indicate that chemokine-derived peptides can show biological activity at pharmacological concentrations. pK-I, in particular, displays the angiogenic activity of full-length vMIP-I, while all peptides appear to have acquired additional properties, stimulating new cellular targets.
Benelli
R
R
Tumor Progression Section, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Barbero
A
A
Buffa
A
A
Aluigi
M G
MG
Masiello
L
L
Morbidelli
L
L
Ziche
M
M
Albini
A
A
Noonan
D
D
D000482:Allantois / Q000098:blood supply; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000097:blood; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D019742:Chemokines, CC / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D003315:Cornea / Q000098:blood supply; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D066298:In Vitro Techniques; D019402:Macrophage Inflammatory Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D011817:Rabbits; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000502:physiology*; D014764:Viral Proteins
C103330:CCR8 protein, human; D015220:Calcium Channels; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D010446:Peptide Fragments; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D014764:Viral Proteins; C108459:vMIP-1 protein, Human herpesvirus 8; D002118:Calcium