The cAMP Pathway Amplifies Early MyD88-Dependent and Type I Interferon-Independent LPS-Induced Interleukin-10 Expression in Mouse Macrophages
Interleukin-10 (IL-10) is a key anti-inflammatory cytokine, secreted by macrophages and other immune cells to attenuate inflammation. Autocrine type I interferons (IFNs) largely mediate the delayed expression of IL-10 by LPS-stimulated macrophages. We have previously shown that IL-10 is synergistica...
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2019/3451461 |
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| author | Orna Ernst Yifat Glucksam-Galnoy Muhammad Athamna Iris Ben-Dror Hadar Ben-Arosh Galit Levy-Rimler Iain D. C. Fraser Tsaffrir Zor |
| author_facet | Orna Ernst Yifat Glucksam-Galnoy Muhammad Athamna Iris Ben-Dror Hadar Ben-Arosh Galit Levy-Rimler Iain D. C. Fraser Tsaffrir Zor |
| author_sort | Orna Ernst |
| collection | DOAJ |
| description | Interleukin-10 (IL-10) is a key anti-inflammatory cytokine, secreted by macrophages and other immune cells to attenuate inflammation. Autocrine type I interferons (IFNs) largely mediate the delayed expression of IL-10 by LPS-stimulated macrophages. We have previously shown that IL-10 is synergistically expressed in macrophages following a costimulus of a TLR agonist and cAMP. We now show that the cAMP pathway directly upregulates IL-10 transcription and plays an important permissive and synergistic role in early, but not late, LPS-stimulated IL-10 mRNA and protein expression in mouse macrophages and in a mouse septic shock model. Our results suggest that the loss of synergism is not due to desensitization of the cAMP inducing signal, and it is not mediated by a positive crosstalk between the cAMP and type I IFN pathways. First, cAMP elevation in LPS-treated cells decreased the secretion of type I IFN. Second, autocrine/paracrine type I IFNs induce IL-10 promoter reporter activity only additively, but not synergistically, with the cAMP pathway. IL-10 promoter reporter activity was synergistically induced by cAMP elevation in macrophages stimulated by an agonist of either TLR4, TLR2/6, or TLR7, receptors which signal via MyD88, but not by an agonist of TLR3 which signals independently of MyD88. Moreover, MyD88 knockout largely reduced the synergistic IL-10 expression, indicating that MyD88 is required for the synergism displayed by LPS with cAMP. This report delineates the temporal regulation of early cAMP-accelerated vs. late type I IFN-dependent IL-10 transcription in LPS-stimulated murine macrophages that can limit inflammation at its onset. |
| format | Article |
| id | doaj-art-886b6554b65c4643a00abb21d2041f34 |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-886b6554b65c4643a00abb21d2041f342025-02-03T05:57:49ZengWileyMediators of Inflammation0962-93511466-18612019-01-01201910.1155/2019/34514613451461The cAMP Pathway Amplifies Early MyD88-Dependent and Type I Interferon-Independent LPS-Induced Interleukin-10 Expression in Mouse MacrophagesOrna Ernst0Yifat Glucksam-Galnoy1Muhammad Athamna2Iris Ben-Dror3Hadar Ben-Arosh4Galit Levy-Rimler5Iain D. C. Fraser6Tsaffrir Zor7Department of Biochemistry & Molecular Biology, School of Neurobiology, Biochemistry & Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv 69978, IsraelDepartment of Biochemistry & Molecular Biology, School of Neurobiology, Biochemistry & Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv 69978, IsraelDepartment of Biochemistry & Molecular Biology, School of Neurobiology, Biochemistry & Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv 69978, IsraelDepartment of Biochemistry & Molecular Biology, School of Neurobiology, Biochemistry & Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv 69978, IsraelDepartment of Biochemistry & Molecular Biology, School of Neurobiology, Biochemistry & Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv 69978, IsraelDepartment of Biochemistry & Molecular Biology, School of Neurobiology, Biochemistry & Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv 69978, IsraelSignaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892 MD, USADepartment of Biochemistry & Molecular Biology, School of Neurobiology, Biochemistry & Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv 69978, IsraelInterleukin-10 (IL-10) is a key anti-inflammatory cytokine, secreted by macrophages and other immune cells to attenuate inflammation. Autocrine type I interferons (IFNs) largely mediate the delayed expression of IL-10 by LPS-stimulated macrophages. We have previously shown that IL-10 is synergistically expressed in macrophages following a costimulus of a TLR agonist and cAMP. We now show that the cAMP pathway directly upregulates IL-10 transcription and plays an important permissive and synergistic role in early, but not late, LPS-stimulated IL-10 mRNA and protein expression in mouse macrophages and in a mouse septic shock model. Our results suggest that the loss of synergism is not due to desensitization of the cAMP inducing signal, and it is not mediated by a positive crosstalk between the cAMP and type I IFN pathways. First, cAMP elevation in LPS-treated cells decreased the secretion of type I IFN. Second, autocrine/paracrine type I IFNs induce IL-10 promoter reporter activity only additively, but not synergistically, with the cAMP pathway. IL-10 promoter reporter activity was synergistically induced by cAMP elevation in macrophages stimulated by an agonist of either TLR4, TLR2/6, or TLR7, receptors which signal via MyD88, but not by an agonist of TLR3 which signals independently of MyD88. Moreover, MyD88 knockout largely reduced the synergistic IL-10 expression, indicating that MyD88 is required for the synergism displayed by LPS with cAMP. This report delineates the temporal regulation of early cAMP-accelerated vs. late type I IFN-dependent IL-10 transcription in LPS-stimulated murine macrophages that can limit inflammation at its onset.http://dx.doi.org/10.1155/2019/3451461 |
| spellingShingle | Orna Ernst Yifat Glucksam-Galnoy Muhammad Athamna Iris Ben-Dror Hadar Ben-Arosh Galit Levy-Rimler Iain D. C. Fraser Tsaffrir Zor The cAMP Pathway Amplifies Early MyD88-Dependent and Type I Interferon-Independent LPS-Induced Interleukin-10 Expression in Mouse Macrophages Mediators of Inflammation |
| title | The cAMP Pathway Amplifies Early MyD88-Dependent and Type I Interferon-Independent LPS-Induced Interleukin-10 Expression in Mouse Macrophages |
| title_full | The cAMP Pathway Amplifies Early MyD88-Dependent and Type I Interferon-Independent LPS-Induced Interleukin-10 Expression in Mouse Macrophages |
| title_fullStr | The cAMP Pathway Amplifies Early MyD88-Dependent and Type I Interferon-Independent LPS-Induced Interleukin-10 Expression in Mouse Macrophages |
| title_full_unstemmed | The cAMP Pathway Amplifies Early MyD88-Dependent and Type I Interferon-Independent LPS-Induced Interleukin-10 Expression in Mouse Macrophages |
| title_short | The cAMP Pathway Amplifies Early MyD88-Dependent and Type I Interferon-Independent LPS-Induced Interleukin-10 Expression in Mouse Macrophages |
| title_sort | camp pathway amplifies early myd88 dependent and type i interferon independent lps induced interleukin 10 expression in mouse macrophages |
| url | http://dx.doi.org/10.1155/2019/3451461 |
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