title: Evaluation of signal transduction pathways in chemoattractant-induced human monocyte chemotaxis.
abstract: The intracellular signaling pathways involved in human monocyte chemotaxis toward a variety of chemoattractant molecules were evaluated using selected pharmacological agents. Neither phosphatidylinositol-3-kinase (P13K) or extracellular signal-regulated kinase (ERK) activity were required for monocyte migration toward monocyte chemoattractant protein-1 (MCP-1), RANTES (Regulated on Activation, Normal T cell Expressed and Secreted), macrophage inflammatory protein-1alpha (MIP-1alpha) or formyl-Met-Leu-Phe (fMLP), since pretreatment with wortmannin or LY294002, or with PD098059, had no effect on the chemotactic response. Addition of forskolin and IBMX significantly attenuated chemotaxis to each of these chemoattractants and was reversed by co-treatment with Rp-cAMP, a competitive inhibitor of cAMP-dependent protein kinase A. Incubation with the protein kinase C (PKC) inhibitor GF109203X-HCl (GF109) did not affect monocyte migration, but pretreatment of monocytes with PMA significantly impaired the response to each of these chemotactic agents. Inhibition by PMA was reversed by co-treatment with GF109, implying that heterologous PKC activation is capable of desensitizing chemokine and fMLP-induced monocyte chemotaxis. These results help to define the signalling pathways involved in human monocyte chemotaxis and suggest pharmacological approaches to evaluating the cross-desensitization of chemoattractant-induced leukocyte migration.
authors.affiliation: Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Fine
authors.forename: H D
authors.initials: HD
authors.lastname: Byrnes
authors.forename: P J
authors.initials: PJ
authors.lastname: Zavodny
authors.forename: R W
authors.initials: RW
authors.lastname: Hipkin
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000494:pharmacology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000494:pharmacology; D002630:Chemotactic Factors / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D002630:Chemotactic Factors; D002867:Chromones; D005419:Flavonoids; D019402:Macrophage Inflammatory Proteins; D009025:Morpholines; D005576:Colforsin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D015056:1-Methyl-3-isobutylxanthine; D000077191:Wortmannin