Interleukin-6 Exacerbates Early Atherosclerosis in Mice

Huber, Sally A.; Sakkinen, Pamela A.; Conze, Dietrich B.; Hardin, Nicholas J.; Tracy, Russell P.

doi:10.1161/01.atv.19.10.2364

Cited by 490 publications

(308 citation statements)

References 24 publications

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“…Both clinical observations and studies in transgenic mice have shown a link between IL-6 overexpression and several pathologic conditions, including atherosclerosis [53][54][55], Alzheimer's disease [56][57][58][59], and rheumatoid arthritis [60][61][62]. It is worth mentioning that statins, which have become important in the treatment of patients with coronary artery disease [63,64] and also have been reported to have beneficial effects in POAG [65], are associated with a reduction in serum levels of IL-6.…”

Section: Discussionmentioning

confidence: 99%

Induction of IL-6 expression by mechanical stress in the trabecular meshwork

Liton

Luna

Bodman

et al. 2005

Biochemical and Biophysical Research Communications

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The trabecular meshwork (TM)/Schlemm's canal (SC) outflow pathway is the tissue responsible for maintaining normal levels of intraocular pressure. In the present study, we investigate the effects of mechanical stress on the expression of IL-6 in the TM meshwork, as well as the effects of this cytokine on outflow pathway function. Application of cyclic mechanical stress to human TM primary cultures resulted in a statistically significant increase in both secretion and transcription of IL-6, compared to nonstressed controls. Addition of TGF-β1, which has been reported to be upregulated in TM cells under mechanical stress, also induced a significant activation of both the transcription and secretion of IL-6. Moreover, anti-TGF-b1 antibodies partially blocked the stretch-induced IL-6 production. Injection of IL-6 into perfused porcine anterior segments resulted in a 30% increase in outflow facility, as well as increased permeability through SC cell monolayers. These results suggest a role for IL-6 in the homeostatic modulation of aqueous humor outflow resistance. KeywordsTrabecular meshwork; Interleukin-6; Mechanical stress; TGF-β1; glaucomaThe trabecular meshwork (TM)/Schlemm's canal (SC) outflow pathway system constitutes the main route by which the aqueous humor exits the anterior chamber of the eye [1]. Maintenance of appropriate levels of aqueous humor outflow resistance through this pathway is critical in sustaining normal levels of intraocular pressure (IOP) [2,3]. Although it has been hypothesized that the TM/SC outflow pathway may respond to transient changes in IOP by altering its resistance to aqueous humor [4][5][6], thereby maintaining normal IOP levels, there is little experimental evidence explaining such potential homeostatic mechanisms.As a result of cyclic fluctuations of IOP with each heartbeat, the conventional outflow pathway is subjected to continuous cycles of stretch and relaxation that might be involved in tissue homeostasis and, consequently, in IOP regulation [7]. It has been well described that changes in IOP exert dramatic effects on the morphology of the outflow pathway [8][9][10][11][12]. Increased IOP results in distention and stretching of the outflow pathway and its contained cells, while decreased IOP leads to relaxation of the tissue. It has also been demonstrated that mechanical stress can trigger certain responses in TM cells, including cytoskeletal changes, induction of gene expression, and activation of regulatory pathways [13][14][15][16][17][18][19][20][21] One of the reported responses to increased IOP in perfused human anterior segments observed by gene array analysis is an increase in interleukin-6 (IL-6) mRNA [16]. IL-6 is well known to increase the permeability of vascular endothelium through effects on the paracellular pathway, induction of matrix metalloproteinases (MMPs), and vesicular trafficking [22][23][24]. This array of effects mediated by IL-6 suggests that this cytokine could affect aqueous humor outflow resistance in the outflow pathway by increasing ...

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Section: Discussionmentioning

confidence: 99%

Induction of IL-6 expression by mechanical stress in the trabecular meshwork

Liton

Luna

Bodman

et al. 2005

Biochemical and Biophysical Research Communications

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“…65 In experimental atherosclerosis, the administration of recombinant IL-6 was found to accelerate atherogenesis in Apoe -/-mice. 66 However, not all animal studies show such activity of IL-6 in the development of atherosclerosis (reviewed by Kleemann et al 52 ). This could be related to its pleiotropic nature, having pro-and antiinflammatory effects.…”

Section: Targeting Chief Proinflammatory Cytokinesmentioning

confidence: 99%

Modulation of Autoimmunity and Atherosclerosis　– Common Targets and Promising Translational Approaches Against Disease –

Ketelhuth

Hansson

2015

Circ J

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“…1 To explore whether inflammation was an integral part of fatty lesion development in the murine model system, we recently studied the effect of weekly interleukin-6 (IL-6) injections on C57Bl/6 and C57Bl/6 apoE ko mice and observed 2-to 5-fold increased lesion size. 2 The greater effect was observed in the wild-type C57Bl/6 strain, suggesting that the very high cholesterol levels observed in apoE ko mice (Ͼ1000 mg/dL) may at least partly mask an underlying inflammation-related mechanism.…”

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confidence: 99%