Human newborns are susceptible to microbial infection and mount poor vaccine responses, yet the mechanisms underlying their susceptibility are incompletely defined. We have previously reported that despite normal basal expression of TLRs and associated signaling intermediates, human neonatal cord blood monocytes demonstrate severe impairment in TNF-α production in response to triacylated (TLR 2/1) and diacylated (TLR 2/6) bacterial lipopeptides (BLPs). We now demonstrate that in marked contrast, BLP-induced synthesis of IL-6, a cytokine with anti-inflammatory and Th2-polarizing properties, is actually greater in neonates than adults. Remarkably, newborn blood plasma confers substantially reduced BLP-induced monocyte synthesis of TNF-α, while preserving IL-6 synthesis, reflecting the presence in neonatal blood plasma of a soluble, low molecular mass inhibitory factor (<10 kDa) that we identify as adenosine, an endogenous purine metabolite with immunomodulatory properties. The neonatal adenosine system also inhibits TNF-α production in response to whole microbial particles known to express TLR2 agonist activity, including Listeria monocytogenes, Escherichia coli (that express BLPs), and zymosan particles. Selective inhibition of neonatal TNF-α production is due to the distinct neonatal adenosine system, including relatively high adenosine concentrations in neonatal blood plasma and heightened sensitivity of neonatal mononuclear cells to adenosine A3 receptor-mediated accumulation of cAMP, a second messenger that inhibits TLR-mediated TNF-α synthesis but preserves IL-6 production. We conclude that the distinct adenosine system of newborns polarizes TLR-mediated cytokine production during the perinatal period and may thereby modulate their innate and adaptive immune responses.
Adenosine is a potent endogenous regulator of inflammation and tissue repair. Adenosine, which is released from injured and hypoxic tissue or in response to toxins and medications, may induce pulmonary fibrosis in mice, presumably via interaction with a specific adenosine receptor. We therefore determined whether adenosine and its receptors contribute to the pathogenesis of hepatic fibrosis. As in other tissues and cell types, adenosine is released in vitro in response to the fibrogenic stimuli ethanol (40 mg dl−1) and methotrexate (100 nM). Adenosine A2A receptors are expressed on rat and human hepatic stellate cell lines and adenosine A2A receptor occupancy promotes collagen production by these cells. Liver sections from mice treated with the hepatotoxins carbon tetrachloride (CCl4) (0.05 ml in oil, 50 : 50 v : v, subcutaneously) and thioacetamide (100 mg kg−1 in PBS, intraperitoneally) released more adenosine than those from untreated mice when cultured ex vivo. Adenosine A2A receptor‐deficient, but not wild‐type or A3 receptor‐deficient, mice are protected from development of hepatic fibrosis following CCl4 or thioacetamide exposure. Similarly, caffeine (50 mg kg−1 day−1, po), a nonselective adenosine receptor antagonist, and ZM241385 (25 mg kg−1 bid), a more selective antagonist of the adenosine A2A receptor, diminished hepatic fibrosis in wild‐type mice exposed to either CCl4 or thioacetamide. These results demonstrate that hepatic adenosine A2A receptors play an active role in the pathogenesis of hepatic fibrosis, and suggest a novel therapeutic target in the treatment and prevention of hepatic cirrhosis. British Journal of Pharmacology (2006) 148, 1144–1155. doi:
Objective. Low-dose weekly methotrexate therapy remains a mainstay in the treatment of inflammatory arthritis. Results of previous studies demonstrated that adenosine, acting at one or more of its receptors, mediates the antiinflammatory effects of methotrexate in animal models of both acute and chronic inflammation. We therefore sought to establish which receptor ( Results. Low-dose weekly methotrexate treatment increased the adenosine concentration in the exudates of all mice studied and reduced leukocyte and tumor necrosis factor ␣ accumulation in the exudates of wildtype mice, but not in those of A 2A or A 3 receptor knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was equally effective at suppressing leukocyte accumulation in A 2A knockout, A 3 knockout, and wild-type mice, indicating that the lack of response was specific for methotrexate and MX-68.Conclusion. These findings confirm that adenosine, acting at A 2A and A 3 receptors, is a potent regulator of inflammation. Moreover, these results provide strong evidence that adenosine, acting at either or both of these receptors, mediates the antiinflammatory effects of methotrexate and its analog MX-68.Low-dose weekly methotrexate is the "gold standard" of therapy in rheumatoid arthritis and other inflammatory diseases. Methotrexate's mechanism of action in the treatment of inflammatory diseases has been the subject of some controversy, although in previous studies, investigators in our group have demonstrated that adenosine mediates the antiinflammatory effects of methotrexate treatment in models of acute and chronic inflammation (1,2). Adenosine, whether released from injured cells or tissues or applied exogenously, regulates inflammation via interaction with one or more of the 4 known receptors for adenosine (A 1 , A 2A , A 2B , and A 3 ), as demonstrated by many in vitro and in vivo pharmacologic studies (for review, see ref.3). The demonstration that adenosine mediates the antiinflammatory effects of methotrexate in in vivo models of acute inflammation rests upon reversal of the antiinflammatory effects of methotrexate, either by enzymatic hydrolysis of adenosine by adenosine deaminase or by administration of adenosine receptor antagonists to reverse the antiinflammatory effects of methotrexate treatment (1,2). Although the antiinflammatory effects of methotrexate are mediated by multiple adenosine receptors in the adjuvant arthritis model of inflammation (2), the identity of the receptor(s) involved in the suppression of inflammation in models of acute inflammation has not been so well characterized.
.Conclusion. These results demonstrate that adenosine A 2A receptors play an active role in the pathogenesis of dermal fibrosis and suggest a novel therapeutic target in the treatment and prevention of dermal fibrosis in diseases such as scleroderma.Adenosine, a product of ATP catabolism, is released from cells and tissues under conditions of stress or hypoxia and is a potent endogenous physiologic and pharmacologic mediator. Adenosine regulates cellular and organ function via interaction with a family of 4 G protein-coupled receptors, A 1 , A 2A , A 2B , and A 3.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.