Interleukin-18 (Interferon-γ–inducing Factor) Is Produced by Osteoblasts and Acts Via Granulocyte/Macrophage Colony-stimulating Factor and Not Via Interferon-γ to Inhibit Osteoclast Formation

Abstract

We have established by differential display polymerase chain reaction of mRNA that interleukin (IL)-18 is expressed by osteoblastic stromal cells. The stromal cell populations used for comparison differed in their ability to promote osteoclast-like multinucleated cell (OCL) formation. mRNA for IL-18 was found to be expressed in greater abundance in lines that were unable to support OCL formation than in supportive cells. Recombinant IL-18 was found to inhibit OCL formation in cocultures of osteoblasts and hemopoietic cells of spleen or bone marrow origin. IL-18 inhibited OCL formation in the presence of osteoclastogenic agents including 1α,25-dihydroxyvitamin D3, prostaglandin E2, parathyroid hormone, IL-1, and IL-11. The inhibitory effect of IL-18 was limited to the early phase of the cocultures, which coincides with proliferation of hemopoietic precursors. IL-18 has been reported to induce interferon-γ (IFN-γ) and granulocyte/macrophage colony-stimulating factor (GM–CSF) production in T cells, and both agents also inhibit OCL formation in vitro. Neutralizing antibodies to GM–CSF were able to rescue IL-18 inhibition of OCL formation, whereas neutralizing antibodies to IFN-γ did not. In cocultures with osteoblasts and spleen cells from IFN-γ receptor type II–deficient mice, IL-18 was found to inhibit OCL formation, indicating that IL-18 acted independently of IFN-γ production: IFN-γ had no effect in these cocultures. Additionally, in cocultures in which spleen cells were derived from receptor-deficient mice and osteoblasts were from wild-type mice and vice versa, we identified that the target cells for IFN-γ inhibition of OCL formation were the hemopoietic cells. The work provides evidence that IL-18 is expressed by osteoblasts and inhibits OCL formation via GM–CSF production and not via IFN-γ production.

Interleukin-18 is a critical factor for vascular endothelial growth factor-enhanced migration in human gastric cancer cell lines

“…This active IL-18 stimulates interferon (IFN)-g production directly, which is known as the IFN-g-inducing factor. IL-18 is produced by macrophages, keratinocytes, dendritic cells as well as by tumor cells (Okamura et al, 1995;Stoll et al, 1997;Udagawa et al, 1997). It has been reported that IL-18 is involved in the immune escape of tumor cells, such as melanoma cells (Cho et al, 2000).…”

Adenoviral delivery of IL-18 binding protein C ameliorates Collagen-Induced Arthritis in mice

“…[4][5][6] A broad range of immuno-regulatory cells, including activated macrophages and dendritic cells but also stromal like cells such as keratinocytes, and osteoblasts, can produce IL-18. [7][8][9] Similar to IL-1, IL-18 is present in cells as a precursor protein, which has to be cleaved to an 18-kDa mature glycoprotein by IL-1b converting enzyme (ICE, caspase-1). Initiation of intracellular signalling by secreted IL-18 starts with the formation of a high-affinity receptor complex, comprising out of the IL-18 binding areceptor chain (IL-18Ra) and the b-chain (IL-18Rb), which itself cannot bind IL-18.…”

Role of interleukin‐18 in experimental group B streptococcal arthritis

“…IL-18 is structurally related to IL-1␤; both cytokines require IL-1␤-converting enzyme for cleavage of the precursor to release the bioactive molecules for IL-1␤ and IL-18 (12,13). Pro-IL-18 expression has been detected in antigen-presenting cells such as activated macrophages, Kupffer cells (11), and dendritic cells (14), as well as articular chondrocytes (15) and osteoblasts (16). IL-18 induces the production of proinflammatory cytokines such as TNF␣ and IL-1 (17).…”

“…IL-18 induces the production of proinflammatory cytokines such as TNF␣ and IL-1 (17). Furthermore, IL-18 stimulates the proliferation of activated T cells and inhibits the formation of osteoclast-like cells (16).…”