Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma.

Feoktistov, Igor; Biaggioni, Italo

doi:10.1172/jci118245

Cited by 335 publications

(260 citation statements)

References 35 publications

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“…Adenosine, which is known to activate mast cells (38), is elevated in ischemia (39). NPY, coreleased with norepinephrine from sympathetic nerve endings, (40), also activates mast cells (41).…”

Section: Discussionmentioning

confidence: 99%

Mast cells: A unique source of renin

Silver

Reid

Mackins

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

175

159

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In addition to the traditional renin-angiotensin system, a great deal of evidence favors the existence of numerous independent tissue-specific renin-angiotensin systems. We report that mast cells are an additional source of renin and constitute a unique extrarenal renin-angiotensin system. We use renin-specific antibodies to demonstrate that cardiac mast cells contain renin. Extending this observation to the human mast cell line HMC-1, we show that these mast cells also express renin. The HMC-1 renin RT-PCR product is 100% homologous to Homo sapiens renin. HMC-1 cells also contain renin protein, as demonstrated both by immunoblot and immunocytochemical analyses. Renin released from HMC-1 cells is active; furthermore, HMC-1 cells are able to synthesize renin. It is known that, in the heart, mast cells are found in the interstitium in close proximity to nerves and myocytes, which both express angiotensin II receptors. Inasmuch as myocardial interstitium contains angiotensinogen and angiotensinconverting enzyme, and because we were able to detect renin only in mast cells, we postulate that the release of renin from cardiac mast cells is the pivotal event triggering local formation of angiotensin II. Because of the ubiquity of mast cells, our results represent a unique paradigm for understanding local renin-angiotensin systems, not just in the heart, but in all tissues. Our findings provide a rationale for targeting mast cells in conjunction with renin-angiotensin system inhibitors in the management of angiotensin II-related dysfunctions.T raditionally the renin-angiotensin system (RAS) has been viewed as a circulating axis, whereby renin is released into the circulation from the kidneys in response to decreased renal perfusion pressure, decreased delivery of NaCl at the macula densa, and͞or increased renal sympathetic nerve activity (1). The rate-limiting step in the formation of angiotensin II (ANG II) is the proteolytic action of renin, which cleaves angiotensinogen (Aogen) to the intermediate angiotensin I (ANG I). ANG I is then converted to ANG II by angiotensin-converting enzyme (ACE) at the endothelial surface (2, 3).In addition to this conventional pathway, many tissues, including heart and brain, are thought to be capable of local ANG II production via tissue-specific RAS (4, 5). Although Aogen, ANG I, and ACE, have been demonstrated in various organs, the presence of renin of extrarenal origin has been more difficult to prove and remains controversial. In this investigation, experiments were designed to determine whether renin could be detected in native tissue other than kidney. Because ANG II plays such a crucial role in cardiovascular disease, we focused our efforts on heart tissue, which we screened for renin by using an established polyclonal anti-renin Ab made to recombinant human renin (6). We found that cardiac mast cells were immunopositive for renin. In addition, we used a cultured mast cell line to extrapolate our observations from fixed heart slices to living cells.Our findings indicate that ma...

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Section: Discussionmentioning

confidence: 99%

Mast cells: A unique source of renin

Silver

Reid

Mackins

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

175

159

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“…The A 2B AR is positively coupled to both adenylyl cyclase and PLC [17][18][19][20] . Results indicate that the activation of PLC, through G q proteins, mediates many of the important functions of A 2B ARs 21,22 .…”

Section: Ar Signalling Pathways and Regulationmentioning

confidence: 99%

“…Activation of the A 2B AR by the non-selective agonist NECA increased inositol phosphate formation in human mast cell line HMC-1 (REF. 20), which is not sensitive to cholera or pertussis toxin but is antagonized by the slightly A 2B AR-selective antagonist enprofylline (3-propylxanthine) 20 . The arachidonic acid pathway was also recently demonstrated to be involved in A 2B AR activation 23 .…”

Section: Ar Signalling Pathways and Regulationmentioning

confidence: 99%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,289

1,361

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Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.

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“…However, the A2 A family of adenosine receptors signal through cAMP and are not coupled to PLC/IP3 Schulte and Fredholm, 2003); thus, A2 B receptors would not be detected in the calcium-imaging experiments described above. The A2 B subclass of adenosine receptors are also positively coupled to cAMP, and can mediate PLC/IP3-dependent increases in intracellular calcium (Ca i 2+ ) in some cell types (Feoktistov and Biaggioni, 1995;Yakel et al, 1993). Using RT-PCR with specific primers for mouse A2 A and A2 B receptors, we detected adenosine receptor mRNA transcripts for both A2 receptor subtypes in mouse SCs in culture (Fig.…”

Section: Premyelinating Mouse Scs Express Functional Adenosine Receptorsmentioning

confidence: 99%

Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells

et al. 2004

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Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron-glia communication are not known. Recent research shows that adenosine is a neuron-glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility that adenosine might have a similar function in communicating between axons and premyelinating SCs. Using a combination of pharmacological and molecular approaches, we found that mouse SCs in culture express functional adenosine receptors and ATP receptors, a far more complex array of purinergic receptors than thought previously. Adenosine, but not ATP, activates ERK/MAPK through stimulation of cAMP-linked A2 A adenosine receptors. Both ATP and adenosine inhibit proliferation of SCs induced by platelet-derived growth factor (PDGF), via mechanisms that are partly independent. In contrast to ATP, adenosine failed to inhibit the differentiation of SCs to the O4+ stage. This indicates that, in addition to ATP, adenosine is an activity-dependent signaling molecule between axons and premyelinating Schwann cells, but that electrical activity, acting through adenosine, has opposite effects on the differentiation of myelinating glia in the PNS and CNS.

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Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma.

Cited by 335 publications

References 35 publications

Mast cells: A unique source of renin

Mast cells: A unique source of renin

Adenosine receptors as therapeutic targets

Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells

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