Inflammatory cytokine production by immunological and foreign body multinucleated giant cells - PubMed (original) (raw)

Inflammatory cytokine production by immunological and foreign body multinucleated giant cells

R Hernandez-Pando et al. Immunology. 2000 Jul.

Abstract

Multinucleated giant cells (MGC) are a common feature of granulomas. The mechanism of their formation has been studied extensively, but their function has not been completely characterized. A new method for the in vivo production of MGC was developed involving subcutaneous injection of microscopic nitrocellulose particles with adsorbed mycobacterial antigens into the footpads of sensitized BALB/c mice (immune [I]-MGC), or by nitrocellulose administration to non-sensitized mice (foreign body [FB]-MGC). The development of granulomas with a highly enriched MGC population was observed 2 weeks after the nitrocellulose injection. MGC were larger with a greater number of nuclei in I-MGC than in FB-MGC. From days 7-28 after nitrocellulose administration, the production of interleukin-1alpha (IL-1alpha) and tumour necrosis factor-alpha (TNF-alpha) was demonstrated in both MGC types by in situ reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. After 2 months, the MGC had ceased production of IL-1alpha and TNF-alpha, but the expression of transforming growth factor-beta (TGF-beta) was very high, occurring together with extensive fibrosis. These results suggest that MGC are an active source of inflammatory cytokines, which can contribute to the initiation, maintenance and down-regulation of granulomatous inflammation induced by immunological and inert substances.

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Figures

Figure 1

Figure 1

Representative light microscopy features during the evolution and formation of multinucleate giant cells (MGC) and their cytokine production. (a) Footpad subcutaneous (s.c.) tissue 7 days after injection of mycobacterial antigens embedded in nitrocellulose microscopic particles. There is an acute and chronic inflammation with few MGC (arrowheads). (b) In this inflammatory infiltrate, there are many interleukin-1α (IL-1α)-immunostained macrophages (Mφ) (arrows). MGC are also positive (arrowheads). (c) Twenty-one days after injection of mycobacterial antigens embedded in nitrocellulose particles, the cellular inflammatory response is constituted predominantly by MGC. (d) In the same lesion shown in Fig. 1(c), all MGC are immunoreactive to IL-1α. (e) The in situ polymerase chain reaction (PCR) analysis shows a high level of transcription of the IL-1α gene in these immune (I)-MGC formed 21 days after nitrocellulose injection. (f) In contrast, at this time-point there is no I-MGC immunostaining to transforming growth factor-β (TGF-β). (g) Sixty days after nitrocellulose injection, there are many MGC-forming nodules surrounded by collagen fibres (arrowheads). (h) In the same lesion as Fig. 1(g), there is no MGC TNF-α immunostaining, but there is TGF-β immunoreactivity (i).

Figure 2

Figure 2

Morphometric analysis of immune (black bars) and foreign body (hatched bars) multinucleated giant cells (MGC). From days 14–45 after subcutaneous (s.c.) injection of nitrocellulose, immune (I)-MGC were significantly larger and had a greater number of nuclei than foreign body (FB)-MGC. The nuclear areas were similar, except at day 14 (*P < 0·05).

Figure 3

Figure 3

Representative electronmicroscopy and immunoelectron microscopy micrographs of multinucleated giant cells (MGC) induced by mycobacterial antigens embedded in nitrocellulose particles. (a) Subcellular structure of MGC 21 days after nitrocellulose injection. The nuclei (N) have condensed chromatin associated with the nuclear membrane, and numerous vacuoles (V) are surrounded by well-developed rough endoplasmic reticulum (arrows). Primary lysosome (L) and long lamellopodia (arrowheads) are also shown. (b) The inner space of the rough endoplasmic reticulum has interleukin-1α (IL-1α) immunoreactivity (arrows), as well as in small- and medium-size vacuoles (*). (c) Near the cell membrane, the cytoplasm and medium-size vacuoles (*) show strong tumour necrosis factor-α (TNF-α) immunolabelling. (d) Subcellular structure of MGC 45 days after nitrocellulose injection. The cytoplasm is well preserved. There are two nuclei: one has condensed chromatin associated with the nuclear membrane (black asterisk) and the other one shows total condensed chromatin (white asterisk), which is a typical apoptotic cell feature.

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