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Selectins promote pain control
Notes
394 Further evaluation of these trends awaits additional analyses of trends in disease severity and detailed investigations into risk factor changes. W.D. Rosamond (3) University of North Carolina Chapel Hill, NC 27599, USA (3) N Engl J Med 1998 ; 339 : 861-7
Selectins promote pain control In peripheral inflamed tissue, an interaction between immune cell-derived opioids and opioid receptors localized on sensory nerve terminals can result in strong, clinically measurable analgesia. A prominent opioid peptide involved in peripheral pain control is P-endorphin. P-endorphin is present in immune cells which migrate preferentially to inflamed sites, where they release the peptide which activates peripheral opioid receptors to inhibit pain. Immune cell recruitment to sites of inflammation is a multi-step process involving the sequential activation of various adhesion molecules located on immune cells and vascular endothelium. Initially, the circulating leukocytes are captured and roll on the endothelial cells of vessels, a process mediated by selectins. Interruption of the leukocyte+ndothelial interaction can block immune cell extravasation. It has now been shown that Such treatment can also influence endogenous pain control in inflammation. Pretreatment of rats with a selectin blocker (fucoidin), inhibits the infiltration of P-endorphin containing immune cells, decreases the P-endorphin content on the inflamed tissue, and abolishes endogenous opioid analgesia. Thus, the immune system uses mechanisms of cell migration not only to fight pathogens, but also to control pain within injured tissue. Pain may be worsened by measures inhibiting the immigration of opioid-producing cells or, conversely, analgesia may be conveyed by promoting adhesive interactions that recruit those cells to injured tissue. H. Machelska (4) Klinik ftir Anaesthesiologie und operative Intensivmedizin Klinikum Benjamin Franklin, Freie Universitit Berlin, 12200 Berlin, Germany
(4) Nature
Med
1998 ; 4 : 1425-8
ROCK blockers inhibit tumor invasion Prevention of invasion and metastasis is critical in the clinical treatment of cancer. These processes occur in multiple steps, and the adhesion of tumor cells to host cell layers and
subsequent transcellular migration are pivotal. The small GTPase Rho controls cell adhesion and motility through the reorganization of the actin cytoskeleton, and regulation of actomyosin contractility in many cellular processes. Among several proteins isolated as putative target molecules of Rho, the ROCK (ROK) family of Rhoassociated serine-threonine protein kinases participates in the induction of focal adhesions and stress fibers in cultured cells, and mediates the CaZ+ sensitization of smooth muscle contraction by enhancing the phosphorylation of the regulatory light chain of myosin. Transfection of hepatoma cells with active mutants of ROCK conferred invasive activity independent of serum and Rho. Conversely, the expression of a dominant negative, kinase-defective ROCK mutant markedly attenuated the invasive phenotype. A specific ROCK inhibitor (Y-27632) blocked both Rho-mediated activation of actomyosin, and the invasive activity of these cells. Furthermore, continuous delivery of this inhibitor using osmotic pumps markedly reduced the dissemination of hepatoma implanted into the peritoneal cavity of syngeneic rats without apparent adverse side effects. These results indicate that ROCK plays a critical role in tumor cell invasion, and demonstrate its potential as a therapeutic target for prevention of cancer invasion and metastasis. K. Itoh (5) Osaka Medical Center Osaka, Japan (5) Nature Med 1999 ; 5 : 221-5
Absence of Jnk causes defective T-cell responses When T-cells are activated, the stress-activated protein kinases are also activated. To determine the biological role of Jnkl , one of the three of the Jnk family of kinases, two of which (Jnkl and 2) are expressed in T-lymphocytes, we eliminated the function of this molecule by gene targeting. These mice were fully viable but their T-cell responses were defective. Effector CD4 T-cell responses can be categorized into T’hl responses, which favor the cellular arm of the immune response and lead to the activation of macrophages and the development of inflammation, and the Th2 response which leads to humoral and antiparasitic immune responses. Strikingly, in mice lacking Jnkl, the Th2 type response was greatly increased although Thl responses could be made. As a result of this, Jr&l-deficient mice exhibited strongerTh2 responses than normal mice. These results suggest that inhibition of Jnkl would lead to increased Th2 responses which might lead to less strong cellular immune responses and stronger humoral responses. This could potentially suggest therapeutic intervention at the level of
394 Further evaluation of these trends awaits additional analyses of trends in disease severity and detailed investigations into risk factor changes. W.D. Rosamond (3) University of North Carolina Chapel Hill, NC 27599, USA (3) N Engl J Med 1998 ; 339 : 861-7
Selectins promote pain control In peripheral inflamed tissue, an interaction between immune cell-derived opioids and opioid receptors localized on sensory nerve terminals can result in strong, clinically measurable analgesia. A prominent opioid peptide involved in peripheral pain control is P-endorphin. P-endorphin is present in immune cells which migrate preferentially to inflamed sites, where they release the peptide which activates peripheral opioid receptors to inhibit pain. Immune cell recruitment to sites of inflammation is a multi-step process involving the sequential activation of various adhesion molecules located on immune cells and vascular endothelium. Initially, the circulating leukocytes are captured and roll on the endothelial cells of vessels, a process mediated by selectins. Interruption of the leukocyte+ndothelial interaction can block immune cell extravasation. It has now been shown that Such treatment can also influence endogenous pain control in inflammation. Pretreatment of rats with a selectin blocker (fucoidin), inhibits the infiltration of P-endorphin containing immune cells, decreases the P-endorphin content on the inflamed tissue, and abolishes endogenous opioid analgesia. Thus, the immune system uses mechanisms of cell migration not only to fight pathogens, but also to control pain within injured tissue. Pain may be worsened by measures inhibiting the immigration of opioid-producing cells or, conversely, analgesia may be conveyed by promoting adhesive interactions that recruit those cells to injured tissue. H. Machelska (4) Klinik ftir Anaesthesiologie und operative Intensivmedizin Klinikum Benjamin Franklin, Freie Universitit Berlin, 12200 Berlin, Germany
(4) Nature
Med
1998 ; 4 : 1425-8
ROCK blockers inhibit tumor invasion Prevention of invasion and metastasis is critical in the clinical treatment of cancer. These processes occur in multiple steps, and the adhesion of tumor cells to host cell layers and
subsequent transcellular migration are pivotal. The small GTPase Rho controls cell adhesion and motility through the reorganization of the actin cytoskeleton, and regulation of actomyosin contractility in many cellular processes. Among several proteins isolated as putative target molecules of Rho, the ROCK (ROK) family of Rhoassociated serine-threonine protein kinases participates in the induction of focal adhesions and stress fibers in cultured cells, and mediates the CaZ+ sensitization of smooth muscle contraction by enhancing the phosphorylation of the regulatory light chain of myosin. Transfection of hepatoma cells with active mutants of ROCK conferred invasive activity independent of serum and Rho. Conversely, the expression of a dominant negative, kinase-defective ROCK mutant markedly attenuated the invasive phenotype. A specific ROCK inhibitor (Y-27632) blocked both Rho-mediated activation of actomyosin, and the invasive activity of these cells. Furthermore, continuous delivery of this inhibitor using osmotic pumps markedly reduced the dissemination of hepatoma implanted into the peritoneal cavity of syngeneic rats without apparent adverse side effects. These results indicate that ROCK plays a critical role in tumor cell invasion, and demonstrate its potential as a therapeutic target for prevention of cancer invasion and metastasis. K. Itoh (5) Osaka Medical Center Osaka, Japan (5) Nature Med 1999 ; 5 : 221-5
Absence of Jnk causes defective T-cell responses When T-cells are activated, the stress-activated protein kinases are also activated. To determine the biological role of Jnkl , one of the three of the Jnk family of kinases, two of which (Jnkl and 2) are expressed in T-lymphocytes, we eliminated the function of this molecule by gene targeting. These mice were fully viable but their T-cell responses were defective. Effector CD4 T-cell responses can be categorized into T’hl responses, which favor the cellular arm of the immune response and lead to the activation of macrophages and the development of inflammation, and the Th2 response which leads to humoral and antiparasitic immune responses. Strikingly, in mice lacking Jnkl, the Th2 type response was greatly increased although Thl responses could be made. As a result of this, Jr&l-deficient mice exhibited strongerTh2 responses than normal mice. These results suggest that inhibition of Jnkl would lead to increased Th2 responses which might lead to less strong cellular immune responses and stronger humoral responses. This could potentially suggest therapeutic intervention at the level of