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NAOKO KANEKO, JUN-ICHI MASUYAMA, HIROYUKI NARA, DAISUKE HIRATA, MASAHIRO IWAMOTO, HITOAKI OKAZAKI, SEIJI MINOTA, and TAKU YOSHIO

ABSTRACT.

Objective. To examine the role of immune complexes in the prostanoid metabolism of glomerular capillary endothelial cells (EC) and platelets in lupus nephritis. Heat aggregated IgG (HA-IgG), instead of immune complexes, was incubated using an in vitro coculture system with human umbilical vein EC, instead of glomerular capillary EC, and platelets. The effect of complement component C1q and a novel imidazole-type thromboxane A₂ (TXA₂) synthetase inhibitor, DP-1904, on this prostanoid metabolism change was also investigated.

Methods. EC monolayers (1.5 ´ 10⁵ cells/well) were incubated with various concentrations of HA-IgG, monomeric IgG, or medium alone for 1 h at 37°C, and then incubated with platelet suspensions (1 ´ 10⁸ cells/ml) for various times. Concentrations of TXB₂ and 6-keto-prostaglandin F_1a (6-keto-PGF_1a), the stable hydrolysis products of TXA₂ and prostaglandin I₂ (PGI₂), respectively, released in the supernatants were measured by ELISA.

Results. HA-IgG bound to EC monolayers produced TXB₂ and 6-keto-PGF_1a in a concentration dependent manner and much more than monomeric IgG or medium alone did. However, the production of 6-keto-PGF_1a stimulated with HA-IgG was much lower than that of TXB₂, indicating a large imbalance between TXA₂ and PGI₂. Preincubation of HA-IgG with purified C1q partially suppressed the production of TXB₂, but not that of 6-keto-PGF_1a. DP-1904 suppressed the production of TXB₂ completely, but by sharp contrast, it dramatically increased the production of 6-keto-PGF_1a from EC and platelets by HA-IgG.

Conclusion. The large imbalance of TXA₂ and PGI₂ produced by the interaction of EC, immune complexes, and platelets may be associated with alterations in glomerular pathological findings and hemodynamics mediated by immune complexes in lupus nephritis. C1q and a TXA₂ synthetase inhibitor may improve the abnormal prostanoid metabolism change of lupus nephritis. (J Rheumatol 2002;29:2106-13)

Key Indexing Terms:

LUPUS NEPHRITIS
THROMBOXANE A₂
PROSTAGLANDIN I₂
ENDOTHELIAL CELLS
IMMUNE COMPLEXES
PLATELETS

Supported by a grant from the Ministry of Health and Welfare, Japan.

N. Kaneko, MD, Assistant; J-I. Masuyama, MD, Assistant Professor; H. Nara, MD, Assistant; D. Hirata, MD, Assistant; M. Iwamoto, MD, Assistant Professor; H. Okazaki, MD, Associate Professor; S. Minota, MD, Professor; T. Yoshio, MD, Assistant Professor.

Address reprint requests to Dr. T. Yoshio, Division of Rheumatology and Clinical Immunology, Jichi Medical School, 3311 Yakushiji, Minamikawachi-machi, Tochigi-ken 329-0498, Japan. E-mail: takuyosh@jichi.ac.jp

Submitted August 22, 2001; revision accepted April 5, 2002.