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Mechanisms of oxyradical production in substance P stimulated rheumatoid synovial cells

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Abstract

We examined the intracellular mechanisms of substance P induced oxyradical production in rheumatoid synovial cells by the luminol-dependent chemiluminescence method. After stimulation with substance P (30 μM), single synovial A (macrophage-like) or B (fibroblast-like) cells released oxyradicals such as superoxide anions (OZ) and/or hypochlorous anions (OCl−) under a microscope equipped with an ultrasensitive photonic image intensifier. The substance P induced oxyradical production was blocked by a tachykinin NK1 (NK1) receptor antagonist, GR82334, GTP-binding protein (G-protein) inactivators, GDPβS and islet-activating protein (IAP), and a phospholipase C (PLC) inhibitor, U-73122. Substance P (30 μM) also induced a transient increase in the intracellular Ca2+ concentration ([Ca2+]i) in both synovial A and B cells as measured by a Ca2+ indicator, fura 2. BAPTA-AM and an inositol-1,4-5-triphosphate (IP3) receptor antagonist, heparin, inhibited the substance P induced increase in [Ca2+]i, but they had no effects on oxyradical production. In contrast to the effects of BAPTA-AM and heparin, protein kinase C (PKC) inhibitors, H-7 and calphostin C, completely inhibited substance P induced oxyradical production without any significant effects on [Ca2+]i increase. These findings suggest that the NK1 receptor/PLC-linked diacylglycerol (DAG) formation with the resulting activation of PKC is the main signal transduction pathway for substance P stimulated oxyradical production in synovial cells.

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Authors and Affiliations

  1. Department of Pharmacology, Kansai Medical University, Moriguchi, 570, Osaka, Japan

    T. Tanabe, H. Otani, K. Mishima & C. Inagaki

  2. Department of Orthopaedic Surgery, Kansai Medical University, Moriguchi, 570, Osaka, Japan

    R. Ogawa

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  1. T. Tanabe
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  2. H. Otani
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  3. K. Mishima
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  4. R. Ogawa
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  5. C. Inagaki
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Tanabe, T., Otani, H., Mishima, K. et al. Mechanisms of oxyradical production in substance P stimulated rheumatoid synovial cells. Rheumatol Int 16, 159–167 (1996). https://doi.org/10.1007/BF01419729

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  • DOI: https://doi.org/10.1007/BF01419729

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