G-protein-coupled receptor independent, immunomodulatory properties of chemokine CXCL9

Gong, Junsong; Nicholls, Erin F.; Elliott, Melissa; Brown, Kelly L.; Hokamp, Karsten; Roche, Fiona; Cheung, Christina; Falsafi, Reza; Brinkman, Fiona S. L.; Bowdish, Dawn M. E.; Hancock, Robert E. W.

doi:10.1016/j.cellimm.2009.11.007

Cited by 10 publications

(10 citation statements)

References 36 publications

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“…Nevertheless, in contrast to monocytes [16], this effect of CXCL9 was G-protein dependent and was mediated by their cognate receptor CXCR3. We did not formally test the effects of CXCL11, a third CXCR3 ligand, in these experiments, but it might be hypothesized that this chemokine displays similar properties under these experimental settings.…”

Section: Discussionmentioning

confidence: 83%

“…Interestingly, a recent report demonstrated also indirect antimicrobial effects of the chemokine CXCL9. In this study CXCL9 induced the expression and secretion of CXCL1 from human monocytes in G-protein independent manner [16]. As CXCL1 is a major chemoattractant for neutrophils, these features of CXCL9 might contribute to its antimicrobial effects in vitro and in vivo.…”

mentioning

confidence: 63%

“…In human monocytes, CXCL9 shares some immunomodulatory capabilities of defensin-like cationic host defense peptides and induces the expression of a variety of immunity genes and cytokines in a CXCR3-independent manner. This was especially shown for CXCL1 (KC) [16]. Thus, this particular chemokine might have direct [14], as well as indirect effects on the infiltration of immune cells during the liver disease.…”

Section: Introductionmentioning

confidence: 93%

“…Furthermore, future studies are warranted to test whether the observed effects are limited to CXCL9 or are also true for the other CXCR3 ligands, as suggested from our in vitro results. Another important aspect for further investigation is the distinction of CXCL9 effects on stellate cells compared to the effects on monocytes, which appear to be CXCR3 independent [16], within the liver.In summary, we here describe a chemokine-chemokine pathway in hepatic stellate cells, which appears to be relevant during liver injury in vivo and leads to the augmented infiltration of neutrophils into the liver. This pathway might therefore be considered as a therapeutic target during liver injury.…”

mentioning

confidence: 99%

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CXCR3 Ligands induce Expression of CXCL1 (KC/murine IL8 homolog) in Mouse Hepatic Stellate Cells

Scholten¹,

samman²,

Sahin³

et al. 2012

J Cel Sci Therapy

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Background and aim: Liver injury leads to infiltration of immune cells and a subsequent activation of hepatic stellate cells. Chemokines are ubiquitous chemotactic proteins which are involved in inflammatory pathways. It has been recently suggested that chemokines can also induce the expression of other chemokines and thereby indirectly regulate immune cell recruitment. We therefore investigated the ability of the chemokine CXCL9 to induce CXCL1, an important neutrophil chemoattractant. Methods:The ability of CXCR3 ligands CXCL9 and CXCL10 to induce CXCL1 expresssion was analyzed in immortalized (GRX) and primary hepatic stellate cells isolated from wild-type and CXCR3-/-mice. Cells were treated with different concentrations of chemokines in the absence and presence of pertussis toxin. Furthermore, mice were treated systemically with CXCL9 and hepatic CXCL1 levels as well as neutrophil infiltration were assessed. Results:Treatment of GRX cells with CXCL9 leads to a dose dependent induction of CXCL1 protein expression. This stimulatory effect was validated in primary hepatic stellate cells (P<0.01). In contrast, stimulation of stellate cells with CCL2 did not result in CXCL1 induction. Increased CXCL1 expression in response to CXCL9 was completely abolished by co-incubation with pertussis toxin and in stellate cells derived from CXCR3-/-mice, the canonical receptor for CXCL9 and CXCL10. Notably, systemic treatment of mice with CXCL9 led to elevated hepatic CXCL1 levels and was associated with enhanced neutrophil infiltration into the liver. Conclusions:The study describes a chemokine-chemokine pathway in hepatic stellate cells which leads to augmented infiltration of neutrophils into the liver during acute liver injury. laboratories (Sulzfeld, Germany). CXCR3 -/-mice were bred for more than 10 generations on the C57Bl/6 background as previously described [17]. Liver injury in wild-type mice was induced by administration of 0.8 ml/kg body weight carbon tetrachloride (CCl 4 ) i.p. Mice were treated concomitantly with 1µg recombinant murine CXCL9 (R&D systems) or vehicle i.p. daily. CXCR3 Ligands induce Isolation and culture of mice hepatic stellate cellsFor screening experiments the murine GRX hepatic stellate cell line was used for in vitro experiments [18,19]. Confirmation experiments were performed in primary murine hepatic stellate cells. These cells were isolated from wild-type C57Bl/6 or CXCR3 -/-mice by a collagenase-pronase two step perfusion method as described [3]. Cell purity was assessed by bright field microscopy and was estimated at 80 -90 %. Experiments were performed after 3 -4 day culturing of primary cells; medium was changed daily to clear cell debris and dead cells. Cells were cultured in DMEM with high-glucose; L-glutamine and sodium pyruvate (PAA Laboratories) supplemented with 10% fetal calf serum (Biochrom KG), 100 IU/ml penicillin, and 100 μg/ml streptomycin (PAA Laboratories). The medium was changed 1 day after initial plating, while cultures were maintained at 37°C, 5% CO 2 . Stim...

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Section: Discussionmentioning

confidence: 83%

mentioning

confidence: 63%

Section: Introductionmentioning

confidence: 93%

mentioning

confidence: 99%

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CXCR3 Ligands induce Expression of CXCL1 (KC/murine IL8 homolog) in Mouse Hepatic Stellate Cells

Scholten¹,

samman²,

Sahin³

et al. 2012

J Cel Sci Therapy

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“…11,12 In recent years, Mig has been studied primarily for its role in autoimmune diseases, angiostasis, and immunomodulation. [13][14][15] The primary protein sequence of murine Mig (MuMig) and human Mig (HuMig) is highly conserved, with a sequence identity of 74%. 16 A high degree of sequence identity also has been observed for the receptor CXCR3, with an 86% identity level.…”

Section: Introductionmentioning

confidence: 99%

Activated expression of the chemokine Mig after chemotherapy contributes to chemotherapy-induced bone marrow suppression and lethal toxicity

Zhu²,

Qian

et al. 2012

Blood

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Host Defence (Antimicrobial) Peptides and Proteins

Wuerth

Hilchie

Brown

et al. 2013

Encyclopedia of Life Sciences

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Host defence (antimicrobial) peptides are small cationic peptides that contain several hydrophobic amino acids. Such peptides typically form amphipathic structures in membrane‐mimicking environments, which contribute to peptide activity on essential membrane‐dependent processes, membrane permeabilisation and/or cell penetration. Host defence peptides (HDPs) have a variety of biological properties, including profound immune‐modulating properties and direct antibacterial, antiviral, antifungal, antiparasitic and anticancer activities. Thus, HDPs are important effectors of the immune system; however, the effector functions of these peptides are often heavily dependent on their microenvironment. The direct antibacterial properties of many peptides are eliminated in the presence of physiologically relevant concentrations of cations and polyanions, although the immune‐modulating properties of these peptides persist under these conditions even in the presence of serum. The immune‐modulating properties are anti‐infective and include chemokine induction and host cell recruitment/differentiation, antiinflammatory activity, promotion of effective adaptive immunity and wound healing activity. Using human peptides as examples, the biological properties of HDPs are discussed herein in an attempt to expose their potential as templates for novel therapeutic agents. Key Concepts: The direct antimicrobial properties of small cationic peptides are often eliminated in the presence of physiologically relevant concentrations of serum and salt; thus they are more accurately described as host defence peptides. The immunomodulatory properties of host defence peptides are complex, have been confirmed in vivo , and contribute to anti‐infective immunity. Humans express several defensins and one cathelicidin (hCAP‐18/LL‐37). Human defensins and cathelicidins are produced by many cell types and have many biological properties, including the ability to destroy pathogens and alter immune responses. Host defence peptides can be modified to improve their biological activities.

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G-protein-coupled receptor independent, immunomodulatory properties of chemokine CXCL9

Cited by 10 publications

References 36 publications

CXCR3 Ligands induce Expression of CXCL1 (KC/murine IL8 homolog) in Mouse Hepatic Stellate Cells

CXCR3 Ligands induce Expression of CXCL1 (KC/murine IL8 homolog) in Mouse Hepatic Stellate Cells

Activated expression of the chemokine Mig after chemotherapy contributes to chemotherapy-induced bone marrow suppression and lethal toxicity

Host Defence (Antimicrobial) Peptides and Proteins

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