The chemokine receptor CCR8 mediates rescue from dexamethasone-induced apoptosis via an ERK-dependent pathway.
Several chemokines have been shown to regulate cellular apoptosis following discrete stimuli. It was previously demonstrated that the CC chemokine CCL1 (I-309) rescues thymic lymphoma cells from apoptosis by unknown mechanisms. The aim of our study was to characterize the role of the CC chemokine receptor 8 (CCR8), the only described receptor for CCL1, in the rescue of murine thymic lymphoma cells and murine thymocytes from dexamethasone (dex)-induced apoptosis. We show here that the CCR8-restricted agonist Kaposi sarcoma-associated herpesvirus-encoded chemokine viral macrophage-inflammatory protein-1 (vMIP-1) rescues thymic lymphoma cells from dex-induced apoptosis, similar to CCL1, and that such rescue is extracellular-regulated kinase-dependent. Although it has been hypothesized that the rescuing effect of CCL1 from apoptosis could be CCR8-mediated, here, we formally demonstrate the role of such receptor as its selective antagonist encoded by the MC148 gene of molluscum contagiosum virus MC148/vMCC-I inhibits v-MIP-1- and CCL1-induced rescue activity. In addition, CCR8 ligands inhibit dex-induced apoptosis of murine thymocytes with potential implications for thymic selection.
Spinetti
Gaia
G
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Monti di Creta 104, 00167 Rome, Italy.
Bernardini
Giovanni
G
Camarda
Grazia
G
Mangoni
Antonella
A
Santoni
Angela
A
Capogrossi
Maurizio C
MC
Napolitano
Monica
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D020013:Calcium Signaling; D054402:Chemokine CCL1; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016399:Lymphoma, T-Cell / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology; D014764:Viral Proteins
C065971:CCL1 protein, human; C103330:CCR8 protein, human; C502258:Ccl1 protein, mouse; D054402:Chemokine CCL1; D019742:Chemokines, CC; C435144:MC148 protein, poxvirus molluscum contagiosum; D019402:Macrophage Inflammatory Proteins; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D014764:Viral Proteins; C108459:vMIP-1 protein, Human herpesvirus 8; D003907:Dexamethasone; D020928:Mitogen-Activated Protein Kinases