Polymorphonuclear leukocyte infiltration and activation into colonic mucosa are believed to play a pivotal role in mediating tissue damage in human ulcerative colitis (UC). Ligands of human CXC chemokine receptor 1 and 2 (CXCR1/R2) are chemoattractants of PMN, and high levels were found in the mucosa of UC patients. To investigate the pathophysiological role played by CXCR2 in experimental UC, we induced chronic experimental colitis in WT and CXCR2 ؊/؊ mice by two consecutive cycles of 4% dextran sulfate sodium administration in drinking water. In wild-type (WT) mice, the chronic relapsing of DSSinduced colitis was characterized by clinical signs and histopathological findings that closely resemble human disease. CXCR2 ؊/؊ mice failed to show PMN infiltration into the mucosa and, consistently with a key role of PMN in mediating tissue damage in UC, showed limited signs of mucosal damage and reduced clinical symptoms. Our data demonstrate that CXCR2 plays a key pathophysiological role in experimental UC, suggesting that CXCR2 activation may represent a relevant pharmacological target for the design of novel pharmacological treatments in human UC.
Carbonic anhydrase IX (CA IX) is a transmembrane protein affecting pH regulation, cell migration/invasion, and survival in hypoxic tumors. Although the pathways related to CA IX have begun to emerge, molecular partners mediating its functions remain largely unknown. Here we characterize the CA IX interactome in hypoxic HEK-293 cells. Most of the identified CA IX-binding partners contain the HEAT/ARM repeat domain and belong to the nuclear transport machinery. We show that the interaction with two of these proteins, namely XPO1 exportin and TNPO1 importin, occurs via the C-terminal region of CA IX and increases with protein phosphorylation. We also demonstrate that nuclear CA IX is enriched in hypoxic cells and is present in renal cell carcinoma tissues. These data place CA IX among the cell-surface signal transducers undergoing nuclear translocation. Accordingly, CA IX interactome involves also CAND1, which participates in both gene transcription and assembly of SCF ubiquitin ligase complexes. It is noteworthy that down-regulation of CAND1 leads to decreased CA IX protein levels apparently via affecting its stability. Our findings provide the first evidence that CA IX interacts with proteins involved in nuclear/cytoplasmic transport, gene transcription, and protein stability, and suggest the existence of nuclear CA IX protein subpopulations with a potential intracellular function, distinct from the crucial CA IX role at the cell surface.
IntroductionThe intensity and duration of an inflammatory process depend on the local balance between pro-and anti-inflammatory factors. Substances of neuronal origin have been the subject of considerable research because they exert specific effects on immune cells and can regulate inflammation. 1,2 In vivo studies of inflammatory diseases have shown that the synthesis of nerve growth factor (NGF) is up-regulated in the cerebrospinal fluid of patients with multiple sclerosis (MS) 3 and in the sera of patients with systemic lupus erythematosus (SLE). 4 A growing number of studies on inflammatory diseases have demonstrated that the inflammatory state is characterized by up-regulation of NGF synthesis. 5,6 Numerous cytokines such as interleukin 1  (IL-1), tumor necrosis factor ␣ (TNF-␣), and IL-6 can induce NGF production in fibroblasts, endothelial cells, and glial cells. [7][8][9] In addition, immune cells involved in innate and acquired immunity show a basal expression of NGF, whose synthesis is enhanced after stimulation with specific antigens and cytokines. [10][11][12][13][14][15] The immune cells that produce NGF also express the specific NGF receptor tyrosine receptor kinase A (TrkA) 16 which, on binding to its ligand, activates intracellular pathways and nuclear factors [17][18][19][20] in a manner similar to what happens in neuronal cells. 21 In vitro, the administration of NGF to purified myeloid-or lymphoid-cell populations influences a wide range of functions: the release of inflammatory mediators, chemotaxis, the production of cytokines and immunoglobulins, proliferation, and survival (for a review see Aloe et al 22 ).In spite of the large number of studies on the in vitro effects of NGF, it is still not clear why NGF is produced in vivo during the inflammation process and how its local synthesis, often in an autocrine fashion, can influence the ongoing immune response.Our recent results on autocrine NGF synthesis in B lymphocytes, which directly regulate the expression and release in these cells 23 of calcitonin gene-related peptide (CGRP), a neuropeptide able to inhibit immune response, indicate that NGF may have an anti-inflammatory action.Specific receptors for CGRP are present in T and B lymphocytes and in macrophages, [24][25][26][27] and several in vitro studies have demonstrated that CGRP is a potent inhibitor of mitogen and antigen-stimulated proliferation of T-cells, 28-31 and of antigen presentation by macrophages. 32,33 In vivo data indicate an anti-inflammatory action of CGRP, since its administration inhibits edema formation induced by inflammatory mediators, prevents the induction of contact hypersensitivity, and influences the migration of monocytes and antigen presentation. [34][35][36] Thus, NGF may influence the inflammatory process either directly, by regulating immune-cell functions, or indirectly, by modulating CGRP synthesis, which in turn affects the immune response. To test this hypothesis, we investigated whether NGF can regulate the synthesis of CGRP in monocytes. These an...
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