Neutrophils and transfected RBL-2H3 cells were used to investigate the mechanism of cross-regulation of the human interleukin-8 (IL-8) receptors CXCR1 and CXCR2 by chemoattractants. In neutrophils, Ca 2؉ mobilization by the CXCR2-specific chemokine, growth-related oncogene ␣ (Gro␣), was desensitized by prior exposure to the chemoattractants N-formylated peptides (fMLP) or a complement cleavage product (C5a). In contrast, growth-related oncogene ␣ did not desensitize the latter receptors. To investigate this phenomenon, CXCR2 was stably expressed in RBL-2H3 cells and mediated phosphoinositide hydrolysis, Ca 2؉ mobilization, chemotaxis, and secretion. In cells co-expressing CXCR2 and receptors for either C5a (C5aR) or fMLP (FR), CXCR2 was cross-phosphorylated and cross-desensitized by C5a and fMLP. However, neither C5aR nor FR was cross-phosphorylated or cross-desensitized by CXCR2 activation, although CXCR1 did mediate this process. Receptor internalization induced by IL-8 was more rapid and occurred at lower doses with CXCR2 than CXCR1, although both receptors mediated equipotent chemotaxis and exocytosis in RBL. Truncation of the cytoplasmic tail of CXCR2 (331T) prolonged its signaling relative to CXCR2, increased its resistance to internalization, and induced phospholipase D activation. 331T was resistant to homologous phosphorylation and cross-phosphorylation but not cross-desensitization of its Ca 2؉ mobilization by fMLP or C5a, indicating an inhibitory site distal to receptor/G protein coupling. In contrast to CXCR2, stimulation of 331T cross-desensitized Ca 2؉ mobilization by both FR and C5aR. CXCR2 and the mutant 331T induced phospholipase C  3 phosphorylation to an extent equivalent to that of CXCR1. Taken together, these results suggest that CXCR1 and CXCR2 bind IL-8 to produce a group of equipotent responses, but their ability to generate other signals, including receptor internalization, cross-desensitization, and phospholipase D activation, are very different. The latter phenomena apparently require prolonged receptor activation, which in the case of CXCR2 is precluded by rapid receptor phosphorylation and internalization. Thus, receptors coupling to identical G proteins may trigger different cellular responses dependent on the length of their signaling time, which can be regulated by receptor phosphorylation.
Adolescent non-suicidal self-injury (NSSI) and suicidality are serious health concerns; however, factors that contribute to the transition from NSSI to suicide ideation and suicide attempts are unclear. To address this gap, we investigated whether demographic characteristics, child maltreatment, and psychiatric factors are associated with the level suicidality among adolescents with a history of self-injury. Participants were three groups of adolescent inpatient self-injurers (n = 397, 317 female), aged 13–18 years (M = 15.44, SD = 1.36): (a) non-ideators (n = 96; no current suicide ideation and no lifetime suicide attempts), (b) suicide ideators (n = 149; current ideation and no lifetime attempts), and (c) suicide attempters (n = 152; current ideation and at least one lifetime attempt). Participants completed interviews assessing psychiatric diagnoses, suicidality, and NSSI characteristics, as well as questionnaires on childhood trauma, psychiatric symptoms, and risky behavior engagement. Depression severity was associated with greater odds being a suicide ideator (p < 0.001, OR = 1.04) and an attempter (p < 0.001, OR = 1.05) compared to a non-ideator. Suicide attempters used more NSSI methods and reported greater risky behavior engagement than non-ideators (p = 0.03, OR = 1.29 and p = 0.03, OR = 1.06, respectively) and ideators (p = 0.015, OR = 1.25 and p = 0.04, OR = 1.05, respectively); attempters used more severe NSSI methods (e.g., burning). Our results identify a wide range of risk markers for increasing lethality in a sample at high risk for suicide mortality; future research is needed to refine risk assessments for adolescent self-injurers and determine the clinical utility of using risk markers for screening and intervention.
Human leukocyte chemoattractant receptors activate chemotactic and cytotoxic pathways to varying degrees and also activate different G-proteins depending on the receptor and the cell-type. To determine the relationship between G-protein usage and the biological and biochemical responses activated, receptors for the chemoattractants formyl peptides (FR), platelet-activating factor (PAFR), and leukotriene B 4 (BLTR) were transfected into RBL-2H3 cells. Pertussis toxin (Ptx) served as a G␣ i inhibitor. These receptors were chosen to represent the spectrum of G i usage as Ptx had differential effects on their ability to induce calcium mobilization, phosphoinositide hydrolysis, and exocytosis with complete inhibition of all responses by FR, intermediate effects on BLTR, and little effect on PAFR. Ptx did not affect ligand-induced phosphorylation of PAFR and BLTR but inhibited phosphorylation of FR. In contrast, chemotaxis to formylmethionylleucylphenylalanine, leukotriene B 4 , and platelet-activating factor was completely blocked by Ptx. Wortmannin, a phosphotidylinositol 3-kinase inhibitor, also completely blocked ligand-induced chemotaxis by all receptors but did not affect calcium mobilization or phosphoinositide hydrolysis; however, it partially blocked the exocytosis response to formylmethionylleucylphenylalanine and the platelet-activating factor. Membrane ruffling and pseudopod extension via the BLTR was also completely inhibited by both Ptx and wortmannin. These data suggest that of the chemoattractant receptors studied, G-protein usage varies with FR being totally dependent on G i , whereas BLTR and PAFR utilize both G i and a Ptxinsensitive G-protein. Both Ptx-sensitive and -insensitive G-protein usage can mediate the activation of phospholipase C, mobilization of intracellular calcium, and exocytosis by chemoattractant receptors. Chemotaxis, however, had an absolute requirement for a G i -mediated pathway.Migration of leukocytes to sites of inflammation is mediated via the activation of G-protein-coupled chemoattractant receptors (1, 2). Chemoattractants at low concentrations elicit shape change, pseudopod extension, and chemotaxis, and at higher doses; many of them also trigger degranulation and generation of superoxide anions (1, 3). Pathways leading to these activities have been shown to have different dose requirements, kinetics and regulation (4, 5), but the role of G-protein usage remains unknown.Formylpeptides (fMLP), 1 platelet-activating factor (PAF), and leukotriene B 4 (LTB 4 ) are potent chemoattractants for neutrophils and to varying degrees also activate exocytosis and generation of superoxide anions (3,4,6). These activities are mediated through G-protein-coupled receptors (FR, PAFR, and BLTR) (2, 7). G-protein usage of chemoattractant receptors was known to be different depending on cell types (1, 8 -10). Previous studies in RBL cells indicated that FR activated G i , whereas PAFR utilized both G i and a Ptx-insensitive G-protein to activate phosphoinositide hydrolysis, calcium mobilizatio...
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