The adenylate cyclase-cAMP-protein kinase A pathway and regulation of the immune response

Kammer, Gary M.

doi:10.1016/0167-5699(88)91220-0

Cited by 492 publications

(253 citation statements)

References 85 publications

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“…IL-12 can transform the activation of macrophage into the development and activation of CD4 + Th1 cells, lead innate immune response to cell-mediated immune response, and magnify the primary inflammatory reaction [9], [28], [29]. Although inflammation is a protective activity, however, under certain conditions such as severe infection, excessive cytokines could cause the collapse of the immune system.…”

Section: Discussionmentioning

confidence: 99%

“…However, it can also be regulated by exogenous drugs. cAMP-inducing drugs were widely used to suppress inflammation, as well as cellular immune responses [9], [10]. In our previous experiments cAMP-inducers such as CTx (cholera toxin) and 8-Bromo-cAMP (8-Br-cAMP, a cellular permeable cAMP) were found to decrease the production of pro-inflammatory cytokines, including TNF-α, IL-6, IL-12, and increase the secretion of anti-inflammatory cytokines, such as IL-10 and IL-1Ra [1], [11].…”

Section: Introductionmentioning

confidence: 99%

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cAMP elevators inhibit LPS-induced IL-12 p40 expression by interfering with phosphorylation of p38 MAPK in Murine Peritoneal Macrophages

et al. 2002

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mediated signaling may play a suppressive role in immune response. We previously found that the cAMPelevators (CTx and 8-Br-cAMP) inhibited IL-12, IL-1a, IL-6 gene expression, but increased the transcriptional levels of IL-10 and IL-1Ra in LPS-treated murine peritoneal macrophages. The present study examined a possible molecular mechanism involved in cAMP elevators-induced inhibition of IL-12 p40 expression in response to LPS. Our data demonstrated that cAMP elevators downregulated IL-12 p40 mRNA expression and IL-12 p70 production in murine peritoneal macrophages. Subsequent studies revealed that cAMP-elevators blocked phosphorylation of p38 MAPK, but did not affect the activity of NF-B binding to . This is the first report that cAMP elevators inhibit LPS-induced IL-12 production by a mechanism that is associated, at least in part, with p38-dependent inhibition by cAMP signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

cAMP elevators inhibit LPS-induced IL-12 p40 expression by interfering with phosphorylation of p38 MAPK in Murine Peritoneal Macrophages

et al. 2002

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“…These alternative activation pathways may be extremely important in lymphocytes, since it is well known that cAMP or analogs of cAMP suppress T-lymphocyte proliferation (32). Also, the suppression by cAMP appears to be mediated by inhibiting IL-2-driven T-cell activation at a discrete point in G, (31,75).…”

Section: Discussionmentioning

confidence: 99%

Promoter activity of the proliferating-cell nuclear antigen gene is associated with inducible CRE-binding proteins in interleukin 2-stimulated T lymphocytes.

Huang¹,

Shipman-Appasamy²,

Orten³

et al. 1994

Mol. Cell. Biol.

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The proliferating-cell nuclear antigen (PCNA) gene encodes an auxiliary factor of DNA polymerase delta and functions in DNA replication during S phase. It is expressed at much higher levels in proliferating cells than in quiescent cells. We have studied the regulatory role of the 5'-flanking sequence of the murine PCNA gene in interleukin 2 (IL-2)-responsive cloned T cells (L2). Analysis of a set of deletion constructs in transient transfection assays measuring heterologous reporter gene (luciferase) activity demonstrated that the 182-bp 5'-flanking region provides full promoter activity in IL-2-stimulated L2 cells. While many elements contribute to PCNA promoter strength in IL-2-stimulated cells, the largest decrease in activity occurred with deletion of the tandem CRE (cyclic AMP response element) binding sites located at nucleotides -37 to -52. With a gel mobility shift assay, several IL-2-inducible DNA-protein complexes were detected, including CREB (CREbinding) and ATFI (activating transcription factor) proteins that are specific for the PCNA-CRE sequence.Methylation interference analysis confirmed specific binding of these proteins to the CRE sites. Mutation at the PCNA-CRE motif abolishes IL-2-inducible binding and reduces substantially PCNA promoter activity.These results indicate that IL-2-stimulated PCNA transcription may be partially mediated by these CRE-binding proteins.The activation of antigen-specific T lymphocytes from Go to S phase usually requires several signals. Initially, antigen interacts with the T-cell antigen receptor, which leads to the transition from Go to GI and the expression of interleukin 2 (IL-2) receptor and lymphokines including IL-2. Further GI progression requires additional signals provided by the interaction of IL-2 with its high-affinity receptor, which results in the expression of genes related to G, activation, and binding of prolactin to its receptor, which results in entry into S phase and DNA replication (11,14,35,38,67).One of the genes expressed during IL-2-driven G, progression is proliferating-cell nuclear antigen (PCNA) (49, 69). PCNA was originally described as a proliferation-associated nuclear antigen that was thought to be expressed in a cellcycle-specific manner (8,47). While PCNA is an auxiliary protein for DNA polymerase delta (leading-strand polymerase) (9, 59) and PCNA-associated immunofluorescence closely parallels [3H]thymidine incorporation during cell cycle progression (42), synthesis and expression of PCNA can be detected in all phases of the cell cycle (G11SG2/M) in proliferating cells, suggesting that the protein is easily extractable when it is not associated with the polymerase (10, 49). Beach and coworkers showed recently that D-type cyclins can directly interact with PCNA and suggested this interaction as one possible mechanism by which the cell cycle machinery could * Corresponding author. Present address:

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“…The intracellular levels of cAMP play a key role in the function of inflammatory and immune cells, since an increase in this second messenger suppresses a broad array of responses in these cells [1][2][3]. Activation of adenylyl cyclase [4][5][6][7] or inhibition of phosphodiesterases [8], the enzymes that hydrolyse cAMP, suppresses the proliferation of T lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Identification of cyclic AMP‐phosphodiesterase variants from the PDE4D gene expressed in human peripheral mononuclear cells

Némoz¹,

Zhang²,

Sette³

et al. 1996

FEBS Letters

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To determine whether the expression of different PDE4D variants is unique to the rat or conserved through evolution, we have characterized the different PDE4D mRNAs expressed in human peripheral blood mononuclear cells. RT-PCR was performed using primers based on rat sequences and mRNAs from mononuclear cells. The specifically amplified fragments had a size identical to that predicted for rat PDEAD1, PDE4D2 and PDE4D3. Sequencing confirmed that these fragments are derived from the human PDE4D gene. Their sequence was highly homologous to that reported for the rat variants, cDNAs corresponding to the entire ORF of human PDE4D2 and PDFAD3 were expressed in mammalian cells, causing a large increase in PDE activity. Western blot analysis of human peripheral blood mononuclear cell extracts demonstrated the presence of proteins corresponding to the recombinant PDE4D1 and PDE4D2. The pattern of splicing and different promoter usage of the PDE4D gene is therefore conserved during evolution, which indicates an important physiological role.

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The adenylate cyclase-cAMP-protein kinase A pathway and regulation of the immune response

Cited by 492 publications

References 85 publications

cAMP elevators inhibit LPS-induced IL-12 p40 expression by interfering with phosphorylation of p38 MAPK in Murine Peritoneal Macrophages

cAMP elevators inhibit LPS-induced IL-12 p40 expression by interfering with phosphorylation of p38 MAPK in Murine Peritoneal Macrophages

Promoter activity of the proliferating-cell nuclear antigen gene is associated with inducible CRE-binding proteins in interleukin 2-stimulated T lymphocytes.

Identification of cyclic AMP‐phosphodiesterase variants from the PDE4D gene expressed in human peripheral mononuclear cells

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