IL-10 inhibits transcription elongation of the human <i>TNF</i> gene in primary macrophages

Smallie, Tim; Ricchetti, Giuseppe A.; Horwood, Nicole J.; Feldmann, Marc; Clark, Andrew R.; Williams, Lynn M.

doi:10.1084/jem.20100414

Cited by 105 publications

(86 citation statements)

References 35 publications

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“…C/EBP, and AMP-dependent transcription factor (34,35). Because Hck appeared to be necessary for LPS-induced cytokine production, the role of Hck in a number of key downstream signaling pathways was examined.…”

Section: Hck Is Not Required For Lps-induced Mapk or Nf-kb Activationmentioning

confidence: 99%

Hck Tyrosine Kinase Regulates TLR4-Induced TNF and IL-6 Production via AP-1

Smolinska

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Urbaniak

et al. 2011

The Journal of Immunology

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The TLRs play a key role in host defense against infection and injury, and mounting evidence suggests that these receptors may also play a role in diseases such autoimmunity, atherosclerosis, and cancer. Activation of TLRs on macrophages results in the production of multiple soluble mediators including the key inflammatory cytokines, TNF and IL-6. Thus, the intracellular signaling mechanism by which TLRs signal is a subject of great interest. As well as activating the NF-κB and MAPK pathways, TLR engagement leads to tyrosine kinase activation within minutes. Src family kinases (SFKs) are the largest nonreceptor tyrosine kinase family with nine members: Src, Hck, Lyn, Fyn, Fgr, Blk, Lck, Yes, and Ylk. The role of the SFKs in TLR signaling has been an area of much controversy, with conflicting findings between studies using chemical inhibitors and knockout mice. Using primary human macrophages in combination with adenoviral overexpression and small interfering RNA knockdown studies, we show that the SFK, Hck, has a pre-eminent role in LPS/TLR4-induced TNF and IL-6 production. Hck kinase mediates TLR4-induced transcription of both TNF and IL-6 by a mechanism that involves neither the NF-κB nor the MAPK pathways, but rather leads to AP-1 binding with a complex of c-fos and JunD. These data highlight the importance of Hck as an active component in LPS-induced TLR signaling and suggest the possibility of targeting this kinase for the alleviation of excessive inflammation.

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Section: Hck Is Not Required For Lps-induced Mapk or Nf-kb Activationmentioning

confidence: 99%

Hck Tyrosine Kinase Regulates TLR4-Induced TNF and IL-6 Production via AP-1

Smolinska

Page

Urbaniak

et al. 2011

The Journal of Immunology

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“…IL-10 induces STAT3 activation and downstream gene expression when it binds with the IL-10 receptor (IL-10R) complex, which is associated with M 2 -polarized macrophages. Furthermore, ligation of IL-10 with its receptor complex directly inhibits the TNF mRNA transcription pathway through STAT3-related factors (72,73).…”

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confidence: 99%

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

et al. 2015

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c Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), induces formation of granulomas, structures in which immune cells and bacteria colocalize. Macrophages are among the most abundant cell types in granulomas and have been shown to serve as both critical bactericidal cells and targets for M. tuberculosis infection and proliferation throughout the course of infection. Very little is known about how these processes are regulated, what controls macrophage microenvironment-specific polarization and plasticity, or why some granulomas control bacteria and others permit bacterial dissemination. We take a computational-biology approach to investigate mechanisms that drive macrophage polarization, function, and bacterial control in granulomas. We define a "macrophage polarization ratio" as a metric to understand how cytokine signaling translates into polarization of single macrophages in a granuloma, which in turn modulates cellular functions, including antimicrobial activity and cytokine production. Ultimately, we extend this macrophage ratio to the tissue scale and define a "granuloma polarization ratio" describing mean polarization measures for entire granulomas. Here we coupled experimental data from nonhuman primate TB granulomas to our computational model, and we predict two novel and testable hypotheses regarding macrophage profiles in TB outcomes. First, the temporal dynamics of granuloma polarization ratios are predictive of granuloma outcome. Second, stable necrotic granulomas with low CFU counts and limited inflammation are characterized by short NF-B signal activation intervals. These results suggest that the dynamics of NF-B signaling is a viable therapeutic target to promote M 1 polarization early during infection and to improve outcome.

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“…Administration of IL-10 abolishes the detrimental effects of high levels of pro-inflammatory cytokines as they can be found in endotoxemic shock or bacterial peritonitis (97,98). It has been shown that IL-10 suppresses the release and production of TNF-a on the transcription level (100). We and others demonstrate additionally that IL-10 also suppresses miRNA-155 (198).…”

Section: Chapter IX Conclusion and Overviewsupporting

confidence: 60%

Pivotal role of Interleukin-10 on microRNA-155 expression in regulation of the monocyte response in hypothermia.

Billeter¹

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IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages

Cited by 105 publications

References 35 publications

Hck Tyrosine Kinase Regulates TLR4-Induced TNF and IL-6 Production via AP-1

Hck Tyrosine Kinase Regulates TLR4-Induced TNF and IL-6 Production via AP-1

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

Pivotal role of Interleukin-10 on microRNA-155 expression in regulation of the monocyte response in hypothermia.

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