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Functional Expression of Formyl Peptide Receptor Family in Human NK Cells¹

Sang Doo Kim,^2* Jung Mo Kim,^2* Seong Ho Jo,^* Ha Young Lee,^* Sun Young Lee,^* Jae Woong Shim,^* Su-Kil Seo, Jeanho Yun,^* and Yoe-Sik Bae^3*

^*Department of Biochemistry, College of Medicine, Dong-A University, Busan, Korea; and Department of Microbiology, College of Medicine, Inje University, Busan, Korea

We determined the expression of the formyl peptide receptor (FPR) family and the functional roles of the FPR family in NK cells. All tested human NK cells express two members of the FPR family (FPR1 and FPR2). The expression of FPR3 was noted to occur in a donor-specific manner. The stimulation of NK cells with FPR family-selective agonists (fMLF (N-formyl-Met-Leu-Phe), MMK-1, F2L, and WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met)) elicited cytolytic activity in resting NK cells, but not in IL-2-activated NK cells; the cytolytic activity was not inhibited by pertussis toxin. The FPR family agonists also stimulated chemotactic migration of IL-2-activated NK cells, but not resting NK cells; the chemotactic migration was completely inhibited by pertussis toxin. WKYMVm stimulates ERK, p38 MAPK, and JNK activities in both resting and IL-2-activated NK cells. WKYMVm-induced chemotactic migration was partially inhibited by PD98059 (2'-amino-3'-methoxyflavone); however, the inhibition of JNK by its selective inhibitor (SP600125, anthra[1,9-cd]pyrazol-6(2H)-one) dramatically inhibited the WKYMVm-induced cytolytic activity. Furthermore, WKYMVm-induced chemotactic migration and cytolytic activity were partly inhibited by FPR family-selective antagonists (cyclosporin H and WRWWWW). Taken together, our findings indicate that human NK cells express functional members of the FPR family, and in turn the activation of the three members of the FPR receptor family elicit cytolytic activity in NK cells, thus suggesting that the receptors are potentially important therapeutic targets for the modulation of NK cell-mediated immune responses.

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.

¹ This work was supported by a Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean government (MOST) (no. R01–2007-000-11241-0), by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2007-313-E00190), and by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea (0920220).

² S.D.K. and J.M.K. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Yoe-Sik Bae, Department of Biochemistry, College of Medicine, Dong-A University, Busan 602-714, Korea. E-mail address: yoesik{at}dau.ac.kr

⁴ Abbreviations used in this paper: FPR, formyl peptide receptor; DC, dendritic cell; fMLF, N-formyl-Met-Leu-Phe; WKYMVm, Trp-Lys-Tyr-Met-Val-D-Met; F2L, Ac-MLGMIKNSLFGSVETWPWQVL; PTX, pertussis toxin; PD98059, 2'-amino-3'-methoxyflavone, SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; SP600125, anthra[1,9-cd]pyrazol-6(2H)-one; LDH, lactate dehydrogenase; CsH, cyclosporin H; WRW⁴, WRWWWWW.