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Regulation of the receptor specificity and function of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted) by dipeptidyl peptidase IV (CD26)-mediated cleavage.

Oravecz T, Pall M, Roderiquez G, Gorrell MD, Ditto M, Nguyen NY, Boykins R, Unsworth E, Norcross MA - J. Exp. Med. (1997)

Bottom Line: The truncated RANTES(3-68) lacked the ability of native RANTES(1-68) to increase the cytosolic calcium concentration in human monocytes, but still induced this response in macrophages activated with macrophage colony-stimulating factor.Analysis of chemokine receptor messenger RNAs and patterns of desensitization of chemokine responses showed that the differential activity of the truncated molecule results from an altered receptor specificity.Our results indicate that CD26-mediated processing together with cell activation-induced changes in receptor expression provides an integrated mechanism for differential cell recruitment and for the regulation of target cell specificity of RANTES, and possibly other chemokines.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematologic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA. tamas@helix.nih.gov

ABSTRACT
CD26 is a leukocyte activation marker that possesses dipeptidyl peptidase IV activity but whose natural substrates and immunological functions have not been clearly defined. Several chemo-kines, including RANTES (regulated on activation, normal T cell expressed and secreted), have now been shown to be substrates for recombinant soluble human CD26. The truncated RANTES(3-68) lacked the ability of native RANTES(1-68) to increase the cytosolic calcium concentration in human monocytes, but still induced this response in macrophages activated with macrophage colony-stimulating factor. Analysis of chemokine receptor messenger RNAs and patterns of desensitization of chemokine responses showed that the differential activity of the truncated molecule results from an altered receptor specificity. RANTES(3-68) showed a reduced activity, relative to that of RANTES(1-68), with cells expressing the recombinant CCR1 chemokine receptor, but retained the ability to stimulate CCR5 receptors and to inhibit the cytopathic effects of HIV-1. Our results indicate that CD26-mediated processing together with cell activation-induced changes in receptor expression provides an integrated mechanism for differential cell recruitment and for the regulation of target cell specificity of RANTES, and possibly other chemokines.

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Reverse transcriptase– PCR analysis of chemokine receptor transcripts in monocytes  cultured in the absence (M) or  presence (M + M-CSF) of  M-CSF. Total cellular RNA was  subjected to reverse transcriptase– PCR analysis as described in Materials and Methods. Control reactions performed without reverse  transcriptase were negative for  each PCR product.
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Figure 3: Reverse transcriptase– PCR analysis of chemokine receptor transcripts in monocytes cultured in the absence (M) or presence (M + M-CSF) of M-CSF. Total cellular RNA was subjected to reverse transcriptase– PCR analysis as described in Materials and Methods. Control reactions performed without reverse transcriptase were negative for each PCR product.

Mentions: To investigate the functional significance of DPPIV-mediated truncation of RANTES, we compared the effects of chemically synthesized RANTES(1–68) and RANTES(3–68) on monocytes and monocyte-derived macrophages. Both resting cells and cells activated with M-CSF were analyzed because reverse transcriptase–PCR revealed marked changes in the abundance of chemokine receptor transcripts in response to M-CSF activation (Fig. 3). In resting cells, transcripts encoding the chemokine receptors CCR1, CCR2b, or CXCR4, as well as control GAPDH mRNA, were readily detectable, whereas CCR5 receptor transcripts were virtually absent. After differentiation to macrophages, the intensity of the CXCR4 and GAPDH signals remained virtually unchanged, whereas the abundance of CCR1 and CCR5 mRNAs increased substantially and the CCR2b transcript virtually disappeared. CCR3 mRNA was not detected in either cell type.


Regulation of the receptor specificity and function of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted) by dipeptidyl peptidase IV (CD26)-mediated cleavage.

Oravecz T, Pall M, Roderiquez G, Gorrell MD, Ditto M, Nguyen NY, Boykins R, Unsworth E, Norcross MA - J. Exp. Med. (1997)

Reverse transcriptase– PCR analysis of chemokine receptor transcripts in monocytes  cultured in the absence (M) or  presence (M + M-CSF) of  M-CSF. Total cellular RNA was  subjected to reverse transcriptase– PCR analysis as described in Materials and Methods. Control reactions performed without reverse  transcriptase were negative for  each PCR product.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199148&req=5

Figure 3: Reverse transcriptase– PCR analysis of chemokine receptor transcripts in monocytes cultured in the absence (M) or presence (M + M-CSF) of M-CSF. Total cellular RNA was subjected to reverse transcriptase– PCR analysis as described in Materials and Methods. Control reactions performed without reverse transcriptase were negative for each PCR product.
Mentions: To investigate the functional significance of DPPIV-mediated truncation of RANTES, we compared the effects of chemically synthesized RANTES(1–68) and RANTES(3–68) on monocytes and monocyte-derived macrophages. Both resting cells and cells activated with M-CSF were analyzed because reverse transcriptase–PCR revealed marked changes in the abundance of chemokine receptor transcripts in response to M-CSF activation (Fig. 3). In resting cells, transcripts encoding the chemokine receptors CCR1, CCR2b, or CXCR4, as well as control GAPDH mRNA, were readily detectable, whereas CCR5 receptor transcripts were virtually absent. After differentiation to macrophages, the intensity of the CXCR4 and GAPDH signals remained virtually unchanged, whereas the abundance of CCR1 and CCR5 mRNAs increased substantially and the CCR2b transcript virtually disappeared. CCR3 mRNA was not detected in either cell type.

Bottom Line: The truncated RANTES(3-68) lacked the ability of native RANTES(1-68) to increase the cytosolic calcium concentration in human monocytes, but still induced this response in macrophages activated with macrophage colony-stimulating factor.Analysis of chemokine receptor messenger RNAs and patterns of desensitization of chemokine responses showed that the differential activity of the truncated molecule results from an altered receptor specificity.Our results indicate that CD26-mediated processing together with cell activation-induced changes in receptor expression provides an integrated mechanism for differential cell recruitment and for the regulation of target cell specificity of RANTES, and possibly other chemokines.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematologic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA. tamas@helix.nih.gov

ABSTRACT
CD26 is a leukocyte activation marker that possesses dipeptidyl peptidase IV activity but whose natural substrates and immunological functions have not been clearly defined. Several chemo-kines, including RANTES (regulated on activation, normal T cell expressed and secreted), have now been shown to be substrates for recombinant soluble human CD26. The truncated RANTES(3-68) lacked the ability of native RANTES(1-68) to increase the cytosolic calcium concentration in human monocytes, but still induced this response in macrophages activated with macrophage colony-stimulating factor. Analysis of chemokine receptor messenger RNAs and patterns of desensitization of chemokine responses showed that the differential activity of the truncated molecule results from an altered receptor specificity. RANTES(3-68) showed a reduced activity, relative to that of RANTES(1-68), with cells expressing the recombinant CCR1 chemokine receptor, but retained the ability to stimulate CCR5 receptors and to inhibit the cytopathic effects of HIV-1. Our results indicate that CD26-mediated processing together with cell activation-induced changes in receptor expression provides an integrated mechanism for differential cell recruitment and for the regulation of target cell specificity of RANTES, and possibly other chemokines.

Show MeSH
Related in: MedlinePlus