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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteoclasts, the cells that resorb bone, develop from hematopoietic precursors of the bone marrow under the control of factors produced in their microenvironment. The cytokine interleukin-6 can promote hematopoiesis and osteoclastogenesis. Interleukin-6 production by bone and marrow stromal cells is suppressed by 17 beta-estradiol in vitro. In mice, estrogen loss (ovariectomy) increased the number of colony-forming units for granulocytes and macrophages, enhanced osteoclast development in ex vivo cultures of marrow, and increased the number of osteoclasts in trabecular bone. These changes were prevented by 17 beta-estradiol or an antibody to interleukin-6. Thus, estrogen loss results in an interleukin-6-mediated stimulation of osteoclastogenesis, which suggests a mechanism for the increased bone resorption in postmenopausal osteoporosis.
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PMID:Increased osteoclast development after estrogen loss: mediation by interleukin-6. 162 Nov

Interleukin 6 (IL-6) exerts well-established effects on cells of the immune system as well as on various other cell types. It has been implicated in the control of connective tissue cells in such conditions as rheumatoid arthritis and osteoporosis. We have investigated the effects of recombinant human interleukin-6 (rhIL-6) on human osteoblastlike cells derived from explants of trabecular bone. ROS 17/2.8 cells were used as an additional osteoblastlike cell model system. We were unable to identify any effects of rhIL-6 (5-5000 pg/ml) on the proliferation, alkaline phosphatase activity. osteocalcin production, or release of cytokines or prostaglandins by either osteoblastlike cell model system. Since we have shown previously that these cells release IL-6 in culture, we used a sheep anti-human IL-6 antibody to investigate the possibility that (1) action of added exogenous IL-6 could be masking endogenous production, and (2) endogenous IL-6 may regulate the effects of osteotropic agents on the osteoblastlike cells. Presence of the antibody exerted no detectable effects on 1,25-(OH)2D3-stimulated alkaline phosphatase or on proliferation or TNF production enhanced by IL-1. Thus IL-6 does not appear to be involved in the regulation of osteoblast activity.
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PMID:Human osteoblastlike cells do not respond to interleukin-6. 170 32

Using 18-week-old and 52-week-old Wistar rats, we examined interleukin-6 (IL-6) production from osteoblasts and bone marrow macrophages treated with medroxyprogesterone acetate (MPA) and/or beta-estradiol. The level of IL-6 production by osteoblasts was increased by treatment with MPA and, reversely, decreased by treatment with beta-estradiol. These changes were especially remarkable in osteoblasts of 52-week-old rats. Additionally, and in contrast, the production of IL-6 by bone marrow macrophages was not significantly changed by treatment with both agents. These data suggest that because the increased production of IL-6 by osteoblasts treated with MPA in opposition with beta-estradiol, MPA should be careful for osteoporosis dependent upon osteoclasts activated by IL-6. Finally, there was a marked difference in the amount of IL-6 produced between osteoblasts and bone marrow macrophages.
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PMID:Effects of medroxyprogesterone acetate and beta-estradiol on interleukin-6 production from osteoblasts and bone marrow macrophages of Wistar rats of different ages. 747 94

Studies in murine models of osteoporosis have suggested the hypothesis that ovarian steroids may control osteoclastic bone remodeling by limiting the production of interleukin-6 (IL-6) from osteoblasts and bone marrow stromal cells. To investigate this hypothesis in a human model, we have examined 12 separate strains of normal human osteoblasts (HOB) and 11 separate strains of human bone marrow stromal cells (HBMSC) and determined whether ovarian steroids regulate the induction of IL-6 by interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) or IL-1 + TNF. Treatment with IL-1, TNF or IL-1 + TNF resulted in the induction of IL-6 from both cell types with IL-1 + TNF inducing a synergistic induction of IL-6 in HOB (24- to 324-fold) and HBMSC (35-288 fold). Addition of 17 beta-estradiol or progesterone did not significantly alter IL-6 messenger RNA or protein levels in either HOB or HBMSC cultures stimulated with IL-1, TNF or IL-1 + TNF. Cultures incubated up to 96 h with the steroids did not affect IL-6 expression. Furthermore ovarian steroids did not affect IL-6 production in either HBMSC cultures representative of preosteoblasts or HOB cultures representative of highly differentiated osteoblasts. Specific chloramphenicol acetyl transferase assays and reverse transcriptase-polymerase chain reaction studies also demonstrated that the lack of an estrogen effect was not due to the failure of HOB to express functional estrogen receptors. Therefore, we conclude that the regulation of human osteoclastic bone remodeling by ovarian steroids does not occur through the direct regulation of IL-6 gene transcription or protein secretion in either early stages of osteoblast differentiation or the differentiated osteoblast.
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PMID:Production of interleukin-6 in human osteoblasts and human bone marrow stromal cells: evidence that induction by interleukin-1 and tumor necrosis factor-alpha is not regulated by ovarian steroids. 764 14

Bone is living tissue perpetually undergoing metabolism in a process known as remodelling, a sequence of cellular events occurring throughout the skeleton. The process is initiated in response to bone resorption by multinucleated osteoclasts. The capacity to stimulate osteoclastic activity is a property common to a multiplicity of hormones and cytokines--e g, parathyroid hormone, vitamin D, thyroxine, interleukin-1 and tumour necrosis factor. There is also a group of growth factors and cytokines, such as interleukin-6 and interleukin-11, that serve as stimulators of osteoclastic recruitment. Following bone resorption by osteoclasts, osteoblasts are recruited to the resorption lacuna, where they secrete osteoid which is then mineralised to form mature bone. The coupling of bone resorption and formation is governed by growth factors embedded in the mineralised bone matrix and released during resorption. These include transforming growth factor beta, insulin-like growth factor. Osteoporosis is caused by imbalance between the resorption and formation phases of the remodelling cycle.
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PMID:[Continuous remodeling of the skeleton. Growth factors and cytokines direct the activity]. 776 May 96

We report a successful treatment with auranofin in a case of elderly-onset Still's disease. The administration of non-steroidal anti-inflammatory drugs, mizoribine and prednisolone were not only insufficient to suppress the disease activity but were followed by the development of multiple gastric ulcers and severe osteoporosis. On the contrary, treatment with auranofin, 9 mg per day, was effective enough to maintain the disease inactive without any side effects. We also found that plasma levels of interleukin-6 and tumor necrosis factor-alpha were significantly elevated in our patient, suggesting a possible involvement of inflammatory cytokines in this disease.
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PMID:Successful treatment with auranofin in a patient with elderly-onset Still's disease. 776 78

Interleukin-6 (IL-6) is a differentiation and growth factor for a variety of cell types and its excessive production plays a major role in the pathogenesis of multiple myeloma and post-menopausal osteoporosis. IL-6, a four-helix bundle cytokine, is believed to interact sequentially with two transmembrane receptors, the low-affinity IL-6 receptor (IL-6R alpha) and the signal transducer gp130, via distinct binding sites. In this paper we show that combined mutations in the predicted A and C helices, previously suggested to establish contacts with gp130, give rise to variants with no bioactivity but unimpaired binding to IL-6R alpha. These mutants behave as full and selective IL-6 receptor antagonists on a variety of human cell lines. Furthermore, a bifacial mutant was generated (called IL-6 super-antagonist) in which the antagonist mutations were combined with amino acid substitutions in the predicted D helix that increase binding for IL-6R alpha. The IL-6 super-antagonist has no bioactivity, but improved first receptor occupancy and, therefore, fully inhibits the wild-type cytokine at low dosage. The demonstration of functionally independent receptor binding sites on IL-6 suggests that it could be possible to design super-antagonists of other helical cytokines which drive the assembly of structurally related multisubunit receptor complexes.
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PMID:Rational design of a receptor super-antagonist of human interleukin-6. 781 26

Both osteoblasts and osteoclasts are derived from progenitors that reside in the bone marrow; osteoblasts belong to the mesenchymal lineage of the marrow stroma, and osteoclasts to the hematopoietic lineage. The development of osteoclasts from their progenitors is dependent on stromal-osteoblastic cells, which are a major source of cytokines that are critical in osteoclastogenesis, such as interleukin-6 and interleukin-11. The production of interleukin-6 by stromal osteoblastic cells, as well as the responsiveness of bone marrow cells to cytokines such as interleukin-6 and interleukin-11, is regulated by sex steroids. When gonadal function is lost, the formation of osteoclasts as well as osteoblasts increases in the marrow, both changes apparently mediated by an increase in the production of interleukin-6 and perhaps by an increase in the responsiveness of bone marrow progenitor cells not only to interleukin-6 but also to other cytokines with osteoclastogenic and osteoblastogenic properties. The cellular activity of the bone marrow is also altered by the process of aging. Specifically, senescence may decrease the ability of the marrow to form osteoblast precursors. The association between the dysregulation of osteoclast or osteoblast development in the marrow and the disruption of the balance between bone resorption and bone formation, resulting in the loss of bone, leads to the following notion. Like homeostasis of other regenerating tissues, homeostasis of bone depends on the orderly replenishment of its cellular constituents. Excessive osteoclastogenesis and inadequate osteoblastogenesis are responsible for the mismatch between the formation and resorption of bone in postmenopausal and age-related osteopenia. The recognition that changes in the numbers of bone cells, rather than changes in the activity of individual cells, form the pathogenetic basis of osteoporosis is a major advance in understanding the mechanism of this disease.
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PMID:Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. 781 67

Interleukin-6 (IL-6) is a pro-inflammatory cytokine with a wide range of functions. Perhaps the most important physiologically is its role as a mediator of the acute phase inflammatory response. Normally, there is little measurable IL-6 in the circulation, but levels increase abruptly to nanogram amounts during an inflammatory process. During aging, it has been proposed that the tight regulation of IL-6 gene expression becomes less effective and levels are measurable even when there is no evidence for inflammation. Several investigators have identified this cytokine as being involved in the pathogenesis of various disease processes and we have suggested that certain age-associated diseases are directly related. Among these are late-life lymphoma and myeloma, osteoporosis and possibly Alzheimer's disease.
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PMID:The role of interleukin-6 in certain age-related diseases. 783 89

The aging process is associated with significant declines in the levels of many hormones and trophic factors including estrogen, testosterone, growth hormone (somatropin, somatotropin) and insulin-like growth factor-1 (IGF-1, somatomedin-1, somatomedin-C). Since the classic age-related changes resemble the signs and symptoms of endocrine deficiency, it has been hypothesised that some of the negative effects of aging are due to these hormonal deficits. Consequently, the potential role of hormonal replacement in reversing the deleterious effects of aging deserves investigation. In old hypogonadal men, preliminary studies have shown that testosterone replacement not only improves libido but also significantly increases musculoskeletal mass and strength. However, adverse effects have included increases in haematocrit and prostate specific antigen. Similarly, short term studies with growth hormone replacement have shown substantial bodyweight gain, particularly in severely malnourished older adults, but longer studies have been limited by adverse effects such as gynaecomastia and carpal tunnel syndrome in a few people. Thus, though both testosterone and growth hormone may have potential roles for frailty syndromes in the elderly, long term clinical trials are needed to confirm these positive effects and assess their safety. On the other hand, the multiple beneficial effects of estrogen replacement in older women such as relieving acute menopausal symptoms and preventing postmenopausal osteoporosis are well recognised. Observational studies also suggest that estrogen may decrease cardiovascular disease. However, the optimum duration of treatment and the best way to administer this hormone are still unknown. Also, estrogen may be less effective in senile osteoporosis which primarily results from age-related bone loss. Traditionally, age-related bone loss has been attributed to impaired vitamin D activation and decreased calcium absorption. Thus, it was thought that such bone losses may be ameliorated by calcium supplementation. However, recent studies suggest that alterations in local factors affecting bone cell function may also be important in the pathogenesis of osteoporosis. An increase in potent bone resorbing factors, such as the cytokines interleukin-1 and interleukin-6, has been recently demonstrated in elderly patients with osteoporosis. In these patients, it has been suggested that there may also be a decrease in bone growth factors such as IGF-1 and transforming growth factor-beta. Accordingly, studies are underway to determine whether these factors may be useful in the prevention of osteoporosis. Other growth factors recently identified which may be important in aging include epidermal growth factor, nerve growth factor and fibroblast growth factor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Trophic factors in aging. Should older people receive hormonal replacement therapy? 807 75


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