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1.  Kinetics of Chemokine-Glycosaminoglycan Interactions Control Neutrophil Migration into the Airspaces of the Lungs 
Chemokine-glycosaminoglycan (GAG) interactions are thought to result in the formation of tissue-bound chemokine gradients. We hypothesized that the binding of chemokines to GAGs would increase neutrophil migration towards CXC-chemokines instilled into lungs of mice. To test this hypothesis we compared neutrophil migration towards rhCXCL8 and two mutant forms of CXCL8, which do not bind to heparin immobilized on a sensor chip. Unexpectedly, when instilled into the lungs of mice the CXCL8 mutants recruited more neutrophils than rhCXCL8. The CXCL8 mutants appeared in plasma at significantly higher concentrations and diffused more rapidly across an extracellular matrix in vitro. A comparison of the murine CXC-chemokines KC and MIP-2 revealed that KC was more effective in recruiting neutrophils into the lungs than MIP-2. KC appeared in plasma at significantly higher concentrations and diffused more rapidly across an extracellular matrix in vitro than MIP-2. In kinetic binding studies, KC, MIP-2, and rhCXCL8 bound heparin differently, with KC associating and dissociating more rapidly from immobilized heparin than the other chemokines. These data suggest that the kinetics of chemokine-GAG interactions contributes to chemokine function in tissues. In the lungs, it appears that chemokines such as CXCL8 or MIP-2, which associate and disassociate slowly from GAGs, form gradients relatively slowly compared to chemokines that either bind GAGs poorly or interact with rapid kinetics. Thus, different types of chemokine gradients may form during an inflammatory response. This suggests a new model whereby GAGs control the spatiotemporal formation of chemokine gradients and neutrophil migration in tissue.
PMCID: PMC4113427  PMID: 20124102
chemokine; glycosaminoglycan; kinetics; neutrophil; lungs; inflammation; rodent
2.  Promiscuous use of CC and CXC chemokine receptors in cell-to-cell fusion mediated by a human immunodeficiency virus type 2 envelope protein. 
Journal of Virology  1997;71(11):8405-8415.
The CC chemokine receptors CCR5, CCR2, and CCR3 and the CXC chemokine receptor CXCR4 have been implicated as CD4-associated cofactors in the entry of primary and cell line-adapted human immunodeficiency virus type 1 (HIV-1) strains. CXCR4 is also a receptor for T-cell-line-adapted, CD4-independent strains of HIV-2. With the exception of this latter example, little has been reported on the entry cofactors used by HIV-2 strains. Here we show that a CD4-dependent, T-cell-line-adapted HIV-2 strain uses CXCR4 and, to a lesser extent, CCR3 for fusion with and infectious entry into cells. In a cell-to-cell fusion assay, the envelope protein of this virus can utilize a wider repertoire of chemokine receptors to induce fusion. These include CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, and CXCR4. Kinetic analysis indicated that cell lines expressing the receptors that support infection, CXCR4 and CCR3, form syncytia more rapidly than do cell lines expressing the other receptors. Nevertheless, although less efficient, fusion with CXCR2 expressing cells was specific, since it was inhibited by antibodies against CXCR2. The extensive use of chemokine receptors in cell-to-cell fusion has implications for understanding the molecular basis of CD4-chemokine receptor-induced lentivirus fusion and may have relevance for syncytium formation and the direct cell-to-cell transfer of virus in vivo.
PMCID: PMC192303  PMID: 9343197
3.  Chemokine-induced eosinophil recruitment. Evidence of a role for endogenous eotaxin in an in vivo allergy model in mouse skin. 
Journal of Clinical Investigation  1997;100(7):1657-1666.
Selective eosinophil recruitment into tissues is a characteristic feature of allergic diseases. Chemokines are effective leukocyte chemoattractants and may play an important role in mediating eosinophil recruitment in various allergic conditions in man. Here, we describe a novel mouse model of eosinophil recruitment in which we have compared the in vivo chemoattractant activity of different C-C chemokines. Furthermore, we describe the use of antibodies to chemokines and receptor blockade to address the endogenous mechanisms involved in eosinophil recruitment in a late-phase allergic reaction in mouse skin. Intradermal injection of mEotaxin and mMIP-1alpha, but not mMCP-1, mRANTES, mMCP-5, or mMIP-1beta, induced significant 111In-eosinophil recruitment in mouse skin. Significant 111In-eosinophil recruitment was also observed in an active cutaneous anaphylactic reaction. Pretreatment of skin sites with antieotaxin antiserum, but not an antiMIP-1alpha antibody, suppressed 111In-eosinophil recruitment in this delayed-onset allergic reaction. Similarly, desensitization of the eosinophil eotaxin receptor CCR3 with mEotaxin, or blockade of the receptor with metRANTES, significantly inhibited 111In-eosinophil recruitment in the allergic reaction. These results demonstrate an important role for endogenous eotaxin in mediating the 111In-eosinophil recruitment in allergic inflammation, and suggest that blockade of the CCR3 receptor is a valid strategy to inhibit eosinophil migration in vivo.
PMCID: PMC508348  PMID: 9312163
5.  A national survey of asthma prevalence, severity, and treatment in Great Britain. 
Archives of Disease in Childhood  1994;70(3):174-178.
Parents of 5472 children aged 5-17 years from 3209 families were interviewed in a nationwide household survey. In the past year, 15.0% of children had wheezed, 2.2% had more than 12 attacks, and 2.3% had experienced a speech limiting attack. Altogether 4.3% were woken more than once a week by wheezing, 13.1% had doctor diagnosed asthma, and 13.6% had been prescribed antiasthmatic drugs in the past year. With increasing age, morbidity related to wheezing declined to a greater extent than annual period prevalence. The prevalence of wheeze varied little by socioeconomic group, but there were marked trends in all three indices of severity towards increased morbidity in poorer families. Diagnostic labelling and drug treatment of wheezy children did not differ substantially with socioeconomic status. Thus, a degree of socioeconomic equality exists in the process of medical care for childhood asthma in Britain. This does not appear to have resulted in equality of outcome.
PMCID: PMC1029735  PMID: 8135558
6.  Role of cysteine62 in DNA recognition by the P50 subunit of NF-kappa B. 
Nucleic Acids Research  1993;21(8):1727-1734.
A powerful chemical modification procedure has been developed to define determinants of DNA recognition by the p50 subunit of NF-kappa B. Differential labelling with [14C] iodoacetate has identified a conserved cysteine residue, Cys62, that was protected from modification by the presence of an oligonucleotide containing the specific recognition site of the protein. To determine the importance of this cysteine residue, each of the conserved cysteines in p50 was changed to serine and the DNA binding properties of the mutant proteins determined. Scatchard analysis indicated that the C62S mutant bound to its DNA recognition site with a 10-fold larger dissociation constant than the wild type protein, while the other two mutants bound with an intermediate affinity. Dissociation rate constant measurements correlated well with the dissociation constants for the wild type, C119S, and C273S p50 proteins, whereas the p50 C62S-DNA complex dissociated anomalously quickly. Competition analyses with oligonucleotide variants of the DNA recognition site and nonspecific E. coli DNA revealed that the C62S p50 mutant had an altered DNA binding site specificity and was impaired in its ability to discriminate between specific and non-specific DNA. Thus the sulphydryl group of Cys62 is an important determinant of DNA recognition by the p50 subunit of NF-kappa B.
PMCID: PMC309407  PMID: 8493089

Results 1-6 (6)