H. Suriki

Blockade of CXCL10 protects mice from acute colitis and enhances crypt cell survival

Crypt cell renewal is essential for normal intestinal homeostasis as well as mucosal regeneration following injury. However, the factors regulating crypt cell growth in pathological conditionsare not fully understood. We report here that the endogenously produced chemokine CXCL10 regulates crypt cell proliferation. CXCL10 was constitutively expressed by basal crypts in mouse colon, but the expression of CXCL10 as well as CXCR3 was enhanced in the epithelium in the proliferative zone after oral administration of dextran sulfate sodium. Neutralization of CXCL10 protected mice from epithelial ulceration by promoting crypt cell survival without evidence of altered immune cell infiltration. Furthermore, recombinant CXCL10 administration into mice inhibited intestinal epithelial cell proliferation. These findings suggest that CXCL10 regulates crypt cell growth to maintain intestinal homeostasis in an autocrine or paracrine fashion. Thus, CXCL10 can be a new therapeutic target for inflammatory bowel disease by controlling the dynamics of epithelial homeostasis.

Regional Differences on Production of Chemokines in Gastric Mucosa Between Helicobacter pylori-Positive Duodenal Ulcer and Gastric Ulcer

It is well known that antrum-predominantgastritis and pan-gastritis occurs in the patients withHelicobacter pylori-positive duodenal ulcer (DU) andgastric ulcer (GU), respectively. However, the role of chemokines in the pathogenesis of thesepathologies is unclear. We examined the regionaldifferences in mucosal chemokine production in patientswith DU and GU. The production of interleukin-8 (IL-8), growth-related gene (GRO) α, andmacrophage inflammatory protein (MIP)-1α wasgreater in the antrum than in the corpus in DU patients.In the patients with GU, monocyte chemoattractantprotein (MCP)-1 levels in the mucosa adjacent to ulcer weregreater than those away for the ulcer in the corpus. Thereduction in chemokine production occurring inassociation with the eradication of H. pylori differed between DU and GU patients in the antrum (IL-8,P = 0.0394; GROα, P = 0.0149; MIP-1α, P =0.0246; MCP-1, P = 0.0087). The data imply a differentpathogenesis may exist for the gastritis present in patients with DU and GU occurring in H.pylori-positive individuals.

Induction of Colitis and Exocrinopathy in Nude Mice Induced by Immunocompetent Cell Transfer from Murine Retrovirus-lnfected Mice

LP-BM5 murine leukemia virus (MuLV) is known to induce murine acquired immunodeficiency syndrome (MAIDS). We have shown that Sjogren syndrome (SS)-like exocrinopathy can be induced in mice with MAIDS and that adoptive transfer of immunocompetent cells of MAIDS mice can induce inflammatory bowel disease (IBD)-like colitis, which we termed “MAIDS colitis,” and exocrinopathy in recipient syngeneic nude mice. To identify which phenotype of cells in MAIDS induces colitis and exocrinopathy in our model, we analyzed adoptive transfer of separated cell fraction into nude mice. LP-BM5 MuLV was inoculated in 4-week-old C57BL/6 (B6) mice intraperitoneally. Eight weeks after infection, lymph node cells from the virus-infected mice were separated into three fractions using magnetic beads as follows: group 1, whole lymph node cells; group2, CD4+ T cells; group3, non-T, non-B (Mac-1+) cells. Each fraction was transferred to B6 nude mice. Four to six weeks after cell transfer the mice were killed and their tissues analyzed histopathologically. All of the mice inoculated with MAIDS lymph node cells (group 1) exhibited colitis and systemic exocrinopathy, and they died within 6 weeks after cell transfer. Transfer of the CD4+ fraction (group 2) induced exocrinopathy but not colitis. Transfer of the non-T, non-B (Mac-1+) cell fraction (group 3) induced colitis but not exocrinopathy. Mac-1+ macrophages and CD4+ T cells of mice with MAIDS play a distinct role in the development of organ-specific autoimmune-like lesions (i.e., ulcerative colitis-like colitis and SS-like exocrinopathy, respectively).

Kinetic analysis of phenotypes of cells and their cytokine expression in the development of colitis in nude mice with MAIDS colitis

S u m m a r y . L P B M 5 m u r i n e l e u k e mi a v i r u s i s k n o w n t . i n d u c e m u ri n e a c q u i r e d i m m u n o d e 丘c i e n c y s y n d r o m e ( M A I D S) ・ W e h a v e s h o w n t h a t a d o p ti v el y t r a n s f e r r e d s p l e e n c ell s o f M A I D S m i c e c a n i n d u c e i n 且a m m a t o r y b o w el d i s e a s e (I B D ) -li k e c o li ti s t e r m e d ” M A I D S c o li ti s ”