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J. Biol. Chem., Vol. 280, Issue 4, 2888-2895, January 28, 2005

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

So-Young Rah, Kwang-Hyun Park, Myung-Kwan Han, Mie-Jae Im, and Uh-Hyun Kim¶||

From the Department of Biochemistry and the ^¶Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju, 561-182, Republic of Korea

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.

Received for publication, August 20, 2004 , and in revised form, November 16, 2004.

^* This work was supported by the Korea Science and Engineering Foundation Grant R01-2000-000-00134-0 (to U.-H. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Microbiology, Chonbuk National University Medical School, Jeonju, 561-182, Republic of Korea.

^|| To whom correspondence should be addressed: Dept. of Biochemistry, Chonbuk National University Medical School, Keumam-dong, Jeonju, 561-182, Republic of Korea. Tel.: 82-63-270-3083; Fax: 82-63-274-9833; E-mail: uhkim{at}chonbuk.ac.kr.

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