Increased expression of chemokine receptor CCR3 and its ligands in ulcerative colitis: the role of colonic epithelial cells inin vitrostudies

Abstract

SummaryHuman colonic epithelial cells express T helper type 1 (Th1)-associated chemoattractants, yet little is known about the production of Th2-associated chemoattractants. CCL11/eotaxin-1, CCL24/eotaxin-2 and CCL26/eotaxin-3 are known to attract CCR3-expressing, Th2-polarized lymphocytes. We studied constitutive and inflammation-induced expression and production of CCR3 together with its ligands in the colon and peripheral blood of patients with inflammatory bowel disease (IBD) by flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). We further defined the regulated expression of these chemokines by RT-PCR and ELISA using cultured human epithelial cell lines. A higher fraction of peripheral T lymphocytes were found to be positive for CCR3 in patients with ulcerative colitis (UC) compared to Crohn's disease (CD), while almost no CCR3 + T cells were found in normal controls (NC). Similarly, higher and more frequent expression of CCR3 was observed in colonic biopsies from patients with UC, regardless of the disease activity, when compared to CD or NCs. Serum CCL11/eotaxin-1 was increased significantly in UC (306 Ϯ 87 pg/ml) and less so in CD (257 Ϯ 43 pg/ml), whereas CCL24/eotaxin-2, and CCL26/eotaxin-3 were increased only in UC. Colonic expression of the three chemokines was minimal in NCs but high in inflammatory bowel diseases (especially UC) and was independent of disease activity. Th2, and to a lesser extent Th1, cytokines were able to induce expression and production of all three eotaxins from colonic epithelial cells in culture. CCR3 and ligands over-expression would appear to be a characteristic of UC. The production of CCR3 ligands by human colonic epithelial cells suggests further that epithelium can play a role in modulating pathological T cell-mediated mucosal inflammation.

An Extraribosomal Function of Ribosomal Protein L13a in Macrophages Resolves Inflammation

“…All of these cytokines show specific roles in diverse aspects of inflammation. For example, controlling the trafficking of activated T lymphocytes (45) and regulatory T cells (Tregs) (46) to inflammatory sites by CCL22; the role of CXCL13 in B cell homing (47) and its correlation with the childhood-onset lupus (48); activation of a large cohort of immune cells by CCL8 (49) and its elevated level in intrinsic asthmatics (50) and finally promotion of LPS-induced lung inflammation (51) and ulcerative colitis (52) by CCR3. Our data from the KO mice showing the elevated levels of these cytokines by macrophage-specific L13a depletion and significant elevation of inflammation in response to endotoxin challenge are highly consistent with these previous reports.…”

Structural, Genetic, and Functional Signatures of Disordered Neuro-Immunological Development in Autism Spectrum Disorder

“…Several of these chemokines have been found to be overexpressed in inflammatory diseases such as ulcerative colitis [30], atopic dermatitis [31], rheumatoid arthritis [32], and in neurocognitive disorders [33]. This suggests an etiological basis for the disordered innate immunity response found in autism [34], particularly as mediated by monocytes [35] and the histologically related microglia [20], [36], [37].…”

Tacrolimus (FK506) suppresses TNF-α-induced CCL2 (MCP-1) and CXCL10 (IP-10) expression via the inhibition of p38 MAP kinase activation in human colonic myofibroblasts

“…Several studies describe the role of CCL2/CCR2 and CXCL10/CXCR3 in the pathophysiology of IBD (41)(42)(43). Immunohistochemical staining of gut biopsy samples from CD patients revealed infiltrating CD4 + T cells and monocytes/ macrophages that are uniformly positive for CCR2 (21).…”