Activation of CD38 by Interleukin-8 Signaling Regulates Intracellular Ca2+ Level and Motility of Lymphokine-activated Killer Cells

• Published in: The Journal of biological chemistry 2005-01, Vol.280 (4), p.2888-2895
• Main Authors: Rah, So-Young, Park, Kwang-Hyun, Han, Myung-Kwan, Im, Mie-Jae, Kim, Uh-Hyun
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - metabolism; ADP-ribosyl Cyclase - biosynthesis; ADP-ribosyl Cyclase - metabolism; ADP-ribosyl Cyclase 1; Antigens, CD - biosynthesis; Antigens, CD - metabolism; Blotting, Western; Calcium - metabolism; Calcium Channels - metabolism; Cell Line; Cell Movement; Cyclic ADP-Ribose - metabolism; Cyclic GMP - metabolism; Dose-Response Relationship, Drug; Gene Expression Regulation; Humans; Inositol 1,4,5-Trisphosphate Receptors; Interleukin-8 - metabolism; Killer Cells, Lymphokine-Activated - metabolism; Kinetics; Membrane Glycoproteins; Models, Biological; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - metabolism; Ryanodine Receptor Calcium Release Channel - metabolism; Tetradecanoylphorbol Acetate - metabolism; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M409592200

CD38 is an ADP-ribosyl cyclase, producing a potent Ca2+ mobilizer cyclic ADP-ribose (cADPR). In this study, we have investigated a role of CD38 and its regulation through interleukin-8 (IL8) signaling in lymphokine-activated killer (LAK) cells. Incubation of LAK cells with IL8 resulted in an increase of cellular cADPR level and a rapid rise of intracellular Ca2+ concentration ([Ca2+]i), which was sustained for a long period of time (>10 min). Preincubation of an antagonistic cADPR analog, 8-Br-cADPR (8-bromo-cyclic adenosine diphosphate ribose), abolished the sustained Ca2+ signal only but not the initial Ca2+ rise. An inositol 1,4,5-trisphosphate (IP3) receptor antagonist blocked both Ca2+ signals. Interestingly, the sustained Ca2+ rise was not observed in the absence of extracellular Ca2+. Functional CD38-null (CD38-) LAK cells showed the initial rapid increase of [Ca2+]i but not the sustained Ca2+ rise in response to IL8 treatment. An increase of cellular cADPR level by cGMP analog, 8-pCPT-cGMP (8-(4-chlorophenylthio)-guanosine-3′,5′-cyclic monophosphate), but not cAMP analog or phorbol 12-myristate 13-acetate was observed. IL8 treatment resulted in the increase of cGMP level that was inhibited by the IP3 receptor blocker but not a protein kinase C inhibitor. cGMP-mediated Ca2+ rise was blocked by 8-Br-cADPR. In addition, IL8-mediated LAK cell migration was inhibited by 8-Br-cADPR and a protein kinase G inhibitor. Consistent with these observations, IL8-induced migration of CD38- LAK cells was not observed. However, direct application of cADPR or 8-pCPT-cGMP stimulated migration of CD38- cells. These results demonstrate that CD38 is stimulated by sequential activation of IL8 receptor, IP3-mediated Ca2+ rise, and cGMP/protein kinase G and that CD38 plays an essential role in IL8-induced migration of LAK cells.