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CLINICAL RESEARCH: PEDIATRIC CARDIOLOGY

Expression of Myeloid-Related Protein-8 and -14 in Patients With Acute Kawasaki Disease

Keiich Hirono, MD^_*, Dirk Foell, MD, Yanlin Xing, MD^_*, Sachiko Miyagawa-Tomita, PhD, Fei Ye, MD^_*, Martina Ahlmann, MD, Thomas Vogl, PhD, Takeshi Futatani, MD^_*, Chen Rui, MD^_*, Xianyi Yu, MD^_*, Kazuhiro Watanabe, MD^_*, Sayaka Wanatabe, MD^_*, Shinichi Tsubata, MD^_*, Keiichiro Uese, MD^_*, Ikuo Hashimoto, MD^_*, Fukiko Ichida, MD^_*,_*, Makoto Nakazawa, MD, Johannes Roth, MD and Toshio Miyawaki, MD^_*

^_* Department of Pediatrics, Toyama University, Toyama, Japan
Department of Pediatrics, Muenster University, Muenster, Germany
Department of Pediatric Cardiology, Tokyo Women’s Medical University, Tokyo, Japan
Institute of Experimental Dermatology, Muenster University, Muenster, Germany.

Manuscript received July 26, 2005; revised manuscript received January 23, 2006, accepted February 14, 2006.

^_* Reprint requests and correspondence: Dr. Fukiko Ichida, Department of Pediatrics, Toyama University, 2630 Sugitani, Toyama, 930-0194 Japan. (Email: fukiko{at}ms.toyama-mpu.ac.jp).

OBJECTIVES: This study investigated patients with acute Kawasaki disease (KD) to validate myeloid-related protein (MRP)-8/MRP-14 as a marker of disease activity and severity of coronary artery lesion development.

BACKGROUND: Both MRP-8 and -14, which are S100-proteins secreted by activated neutrophils and monocytes, bind specifically to endothelial cells and induce thrombogenic and inflammatory responses in a variety of disease conditions.

METHODS: We investigated 61 patients with acute KD and examined sequential changes in serum levels of MRP-8/MRP-14, messenger ribonucleic acid (mRNA) expression of MRP-8 and -14 in circulating granulocytes and monocytes, and amounts of MRP-8/MRP-14 bound to circulating endothelial cells.

RESULTS: The serum MRP-8/MRP-14 levels as well as mRNA expressions of MRP-8 and -14 in granulocytes were strongly upregulated during the early stage of acute KD, and decreased dramatically within 24 h of intravenous immune globulin therapy (p < 0.05) in 45 responders. In contrast, in 16 nonresponders both of these increased after the initial treatment. The number of MRP-8/MRP-14–positive circulating endothelial cells was higher in patients with acute KD than in control patients and increased significantly by 2 weeks after the onset of KD, especially in patients in whom coronary artery lesions developed.

CONCLUSIONS: We show for the first time that MRP-8/MRP-14 are exclusively secreted by granulocytes in patients with acute KD, and intravenous immune globulin treatment suppresses their gene expression. Serum levels of MRP-8/MRP-14 may be useful markers of disease activity, and the levels of MRP-8/MRP-14–positive circulating endothelial cell may predict the severity of vasculitis, confirming an important role for distinct inflammatory reactions in endothelium.

Abbreviations and Acronyms   CAL = coronary artery lesions   CRP = C-reactive protein   IVIG = intravenous immune globulin   KD = Kawasaki disease   mRNA = messenger ribonucleic acid   MRP = myeloid-related protein   PBS = phosphate-buffered saline   PCR = polymerase chain reaction   PMA = phorbol 12-myristate 13-acetate   RT = reverse transcriptase   TNF = tumor necrosis factor   WBC = white blood cells

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