Tissue-Specific Mechanisms Control the Retention of IL-8 in Lungs and Skin

Frevert, Charles W.; Goodman, Richard B.; Kinsella, Michael G.; Kajikawa, Osamu; Ballman, Kimberly; Clark‐Lewis, Ian; Proudfoot, Amanda E. I.; Wells, Timothy N. C.; Martin, Thomas R.

doi:10.4049/jimmunol.168.7.3550

Cited by 37 publications

(36 citation statements)

References 46 publications

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“…Although we do not know the exact physiological concentrations of these chemokines in vivo, their long t 1/2 could ensure their effectiveness in inducing ASMCs proliferation or enhancing their survival. Moreover, using a rabbit model, Frevert et al (19) have shown that IL-8 is retained in the lungs to a much higher levels than in other tissues such as the skin, and the dimerization of IL-8 plays a role in this process. Knowing that, one can predict that effective levels of IL-8 within the lung tissue could be reached upon its enhanced production and accumulation with time.…”

Section: Discussionmentioning

confidence: 99%

CC and CXC Chemokines Induce Airway Smooth Muscle Proliferation and Survival

Halwani

Al-Abri

Béland

et al. 2011

The Journal of Immunology

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The increase in airway smooth muscle (ASM) mass is a major structural change in asthma. This increase has been attributed to ASM cell (ASMC) hyperplasia and hypertrophy. The distance between ASMC and the epithelium is reduced, suggesting migration of smooth muscle cells toward the epithelium. Recent studies have suggested a role of chemokines in ASMC migration toward the epithelium; however, chemokines have other biological effects. The objective of the current study is to test the hypothesis that chemokines (eotaxin, RANTES, IL-8, and MIP-1α) can directly influence ASMC mass by increasing the rate of proliferation or enhancing the survival of these cells. Human ASMCs were exposed to different concentrations of eotaxin, RANTES, IL-8, or MIP-1α. To test for proliferation, matched control and stimulated ASMC were pulsed with [3H]thymidine, or ASMCs were stained with BrdU and then analyzed with flow cytometry. Apoptosis was measured using Annexin V staining and flow cytometry. Expression of phosphorylated p42/p44 and MAPKs was assessed by Western blot. In a concentration-dependent manner, chemokines including eotaxin, RANTES, IL-8, and MIP-1α increased ASMC’s [3H]thymidine incorporation and DNA synthesis. IL-8, eotaxin, and MIP-1α decreased the rate of apoptosis of ASMCs compared with the matched controls. A significant increase in phosphorylated p42/p44 MAPKs was seen after treating ASMCs with RANTES and eotaxin. Moreover, inhibition of p42/p44 MAPK phosphorylation reduced the level of chemokine-induced ASM proliferation. We conclude that chemokines might contribute to airway remodeling seen in asthma by enhancing the number and survival of ASMCs.

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Section: Discussionmentioning

confidence: 99%

CC and CXC Chemokines Induce Airway Smooth Muscle Proliferation and Survival

Halwani

Al-Abri

Béland

et al. 2011

The Journal of Immunology

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“…To test this hypothesis, we instilled 12 μg each of LukS-PV and LukF-PV (i.e., 0.34 nmol of LukS-PV and 0.32 nmol of LukF-PV), amounts comparable to that produced during USA300 infection of rabbit lungs (Fig. 2I), endotracheally into lungs of normal rabbits and neutropenic (vinblastine-treated) rabbits (32). Because both LukS-PV and LukF-PV are required for biological activity (6, 7), each toxin subunit alone was used as a negative control.…”

Section: Pvl Causes Lung Inflammation and Injury By Pmn-dependentmentioning

confidence: 99%

Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury

Diep

Chan

Tattevin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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308

345

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Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is epidemic in the United States, even rivaling HIV/AIDS in its public health impact. The pandemic clone USA300, like other CA-MRSA strains, expresses Panton-Valentine leukocidin (PVL), a pore-forming toxin that targets polymorphonuclear leukocytes (PMNs). PVL is thought to play a key role in the pathogenesis of necrotizing pneumonia, but data from rodent infection models are inconclusive. Rodent PMNs are less susceptible than human PMNs to PVL-induced cytolysis, whereas rabbit PMNs, like those of humans, are highly susceptible to PVL-induced cytolysis. This difference in target cell susceptibility could affect results of experimental models. Therefore, we developed a rabbit model of necrotizing pneumonia to compare the virulence of a USA300 wild-type strain with that of isogenic PVL-deletion mutant and -complemented strains. PVL enhanced the capacity of USA300 to cause severe lung necrosis, pulmonary edema, alveolar hemorrhage, hemoptysis, and death, hallmark clinical features of fatal human necrotizing pneumonia. Purified PVL instilled directly into the lung caused lung inflammation and injury by recruiting and lysing PMNs, which damage the lung by releasing cytotoxic granule contents. These findings provide insights into the mechanism of PVL-induced lung injury and inflammation and demonstrate the utility of the rabbit for studying PVL-mediated pathogenesis.

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“…IL-8 dimerization is sensitive to solution conditions, and the reported dissociation constants (K d ) vary by as much as 160-fold (0.1-16 M), indicating that IL-8 could easily dimerize under in vivo conditions (7,8). A variety of in vitro cell-based and in vivo studies also suggest dimerization of IL-8 on binding to GAGs (9,10). IL-8 is active for GPCR function at nanomolar concentrations in in vitro cell-based assays, suggesting that IL-8 binds its receptor as a monomer.…”

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confidence: 99%

Dimer Dissociation Is Essential for Interleukin-8 (IL-8) Binding to CXCR1 Receptor

Fernando

Chin

Rösgen

et al. 2004

Journal of Biological Chemistry

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Chemokines play a fundamental role in trafficking of immune cells and in host defense against infection. The role of chemokines in the recruitment process is highly regulated spatially and temporally and involves interactions with G protein-coupled receptors and cell surface glycosaminoglycans. The dynamic equilibrium between chemokine monomers and dimers, both free in solution and in cell surface-bound forms, regulates different components of recruitment such as chemotaxis and receptor signaling. The binding and activity of the chemokine interleukin-8 (IL-8) for its receptors, previously studied using "trapped" non-associating monomers and non-dissociating dimers, show that the monomer has a native-like function but support conflicting roles for the dimer. We have measured the binding of native IL-8 to the CXCR1 N-domain, using isothermal titration calorimetry and sedimentation equilibrium techniques. The N-domain constitutes a critical binding site, and IL-8 binding affinity to the receptor N-domain is in the same concentration range as the IL-8 monomerdimer equilibrium. We observed that only the IL-8 monomer, and not the dimer, is competent in binding the receptor N-domain. Based on our results, we propose that IL-8 dimerization functions as a negative regulator for the receptor function and as a positive regulator for binding to glycosaminoglycans and that both play a role in the neutrophil recruitment process.

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Tissue-Specific Mechanisms Control the Retention of IL-8 in Lungs and Skin

Cited by 37 publications

References 46 publications

CC and CXC Chemokines Induce Airway Smooth Muscle Proliferation and Survival

CC and CXC Chemokines Induce Airway Smooth Muscle Proliferation and Survival

Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury

Dimer Dissociation Is Essential for Interleukin-8 (IL-8) Binding to CXCR1 Receptor

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