Biomedical subjects

E Mizoguchi

Publications and source records attributed to E Mizoguchi.

At least 19 recordsLinked to original sources

PubMed2004

Paradoxical roles of different nitric oxide synthase isoforms in colonic injury.

Nitric oxide (NO) is a free radical that is largely produced by three isoforms of NO synthase (NOS): neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). NO regulates numerous processes in the gastrointestinal tract; however, the overall role that NO plays in intestinal inflammation is unclear. NO is upregulated in both ulcerative colitis and Crohn's disease as well as in animal models of colitis. There have been conflicting reports on whether NO protects or exacerbates injury in colitis or is simply a marker of inflammation. To determine whether the site, timing, and level of NO production modulate the effect on the inflammatory responses, the dextran sodium sulfate model of colitis was assessed in murine lines rendered deficient in iNOS, nNOS, eNOS, or e/nNOS by targeted gene disruption. The loss of nNOS resulted in more severe disease and increased mortality, whereas the loss of eNOS or iNOS was protective. Furthermore, concomitant loss of eNOS reversed the susceptibility found in nNOS-/- mice. Deficiencies in specific NOS isoforms led to distinctive alterations of inflammatory responses, including changes in leukocyte recruitment and alterations in colonic lymphocyte populations. The present studies indicate that NO produced by individual NOS isoforms plays different roles in modulating an inflammatory process.

Animals↗

PubMed2002

The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease.

The balance between pro and antiinflammatory cytokines secreted by T cells regulates both the initiation and perpetuation of inflammatory bowel diseases (IBD). In particular, the balance between interferon (IFN)-gamma/interleukin (IL)-4 and transforming growth factor (TGF)-beta activity controls chronic intestinal inflammation. However, the molecular pathways that evoke these responses are not well understood. Here, we describe a critical role for the transcription factor T-bet in controlling the mucosal cytokine balance and clinical disease. We studied the expression and function of T-bet in patients with IBD and in mucosal T cells in various T helper (Th)1- and Th2-mediated animal models of chronic intestinal inflammation by taking advantage of mice that lack T-bet and retroviral transduction techniques, respectively. Whereas retroviral transduction of T-bet in CD62L(+) CD4(+) T cells exacerbated colitis in reconstituted SCID mice, T-bet-deficient T cells failed to induce colitis in adoptive transfer experiments suggesting that overexpression of T-bet is essential and sufficient to promote Th1-mediated colitis in vivo. Furthermore, T-bet-deficient CD62L(-) CD4(+) T cells showed enhanced protective functions in Th1-mediated colitis and exhibited increased TGF-beta signaling suggesting that a T-bet driven pathway of T cell activation controls the intestinal balance between IFN-gamma/IL-4 and TGF-beta responses and the development of chronic intestinal inflammation in T cell-mediated colitis. Furthermore, TGF-beta was found to suppress T-bet expression suggesting a reciprocal relationship between TGF-beta and T-bet in mucosal T cells. In summary, our data suggest a key regulatory role of T-bet in the pathogenesis of T cell-mediated colitis. Specific targeting of this pathway may be a promising novel approach for the treatment of patients with Crohn's disease and other autoimmune diseases mediated by Th1 T lymphocytes.

Adult↗

PubMed2001

MHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, intestinal macrophages, and dendritic cells.

The neonatal Fc receptor (FcRn) for IgG, an MHC class I-related molecule, functions to transport IgG across polarized epithelial cells and protect IgG from degradation. However, little is known about whether FcRn is functionally expressed in immune cells. We show here that FcRn mRNA was identifiable in human monocytes, macrophages, and dendritic cells. FcRn heavy chain was detectable as a 45-kDa protein in monocytic U937 and THP-1 cells and in purified human intestinal macrophages, peripheral blood monocytes, and dendritic cells by Western blot analysis. FcRn colocalized in vivo with macrosialin (CD68) and Ncl-Macro, two macrophage markers, in the lamina propria of human small intestine. The heavy chain of FcRn was associated with the beta(2)-microglobulin (beta(2)m) light chain in U937 and THP-1 cells. FcRn bound human IgG at pH 6.0, but not at pH 7.5. This binding could be inhibited by human IgG Fc, but not Fab. FcRn could be detected on the cell surface of activated, but not resting, THP-1 cells. Furthermore, FcRn was uniformly present intracellularly in all blood monocytes and intestinal macrophages. FcRn was detectable on the cell surface of a significant fraction of monocytes at lower levels and on a small subset of tissue macrophages that expressed high levels of FcRn on the cell surface. These data show that FcRn is functionally expressed and its cellular distribution is regulated in monocytes, macrophages, and dendritic cells, suggesting that it may confer novel IgG binding functions upon these cell types relative to typical Fc gamma Rs: Fc gamma RI, Fc gamma RII, and Fc gamma RIII.

Adult↗

PubMed2001

Development of chronic colitis is dependent on the cytokine MIF.

The cytokine macrophage-migration inhibitory factor (MIF) is secreted by a number of cell types upon induction by lipopolysaccharide (LPS). Because colitis is dependent on interplay between the mucosal immune system and intestinal bacteria, we investigated the role of MIF in experimental colitis. MIF-deficient mice failed to develop disease, but reconstitution of MIF-deficient mice with wild-type innate immune cells restored colitis. In addition, established colitis could be treated with anti-MIF immunoglobulins. Thus, murine colitis is dependent on continuous MIF production by the innate immune system. Because we found increased plasma MIF concentrations in patients with Crohn's disease, these data suggested that MIF is a new target for intervention in Crohn's disease.

Adoptive Transfer↗

PubMed2001

An obligate role for T-cell receptor alphabeta+ T cells but not T-cell receptor gammadelta+ T cells, B cells, or CD40/CD40L interactions in a mouse model of atopic dermatitis.

BACKGROUND: We recently described a murine model of atopic dermatitis (AD) elicited by epicutaneous sensitization with ovalbumin (OVA). The skin lesions in these mice were characterized by a dermal infiltrate consisting of eosinophils and T cells and by increased expression of the TH2 cytokines IL-4 and IL-5. Epicutaneous sensitization induces a rise in the levels of serum total IgE and OVA-specific antibodies, further indicating that it elicits a predominantly TH2 response. OBJECTIVE: This study was undertaken to assess the roles of T cells, B cells, and CD40L-CD40 interactions in AD. METHODS: Mice with targeted gene deletions were sensitized with OVA. Histologic and immunohistochemical examinations, as well as measurements of IL-4 mRNA, were performed on OVA-sensitized skin. Total and antigen-specific serum IgE levels were determined. RESULTS: RAG2(-/-) mice, which lack both T and B cells, did not exhibit cellular infiltration, induction of dermal IL-4 mRNA, or elevation of serum IgE after OVA sensitization; all of these features were present in B-cell-deficient IgH(-/-) mice. T-cell receptor alpha(-/-) mice did not display cellular infiltration, IL-4 mRNA expression, or increased IgE levels after OVA sensitization, but these responses were elicited in T-cell receptor delta(-/-) mice after sensitization. Absence of CD40 had no effect on these responses. CONCLUSION: These results suggest that alphabeta T cells, but not gammadelta T cells, B cells, or CD40L-CD40 interactions, are critical for skin inflammation and the TH2 response in AD.

Animals↗

PubMed2000

Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte-associated Th2-type immune response in the intestine.

The chemokine receptors CCR2 and CCR5 and their respective ligands regulate leukocyte chemotaxis and activation. To determine the role of these chemokine receptors in the regulation of the intestinal immune response, we induced colitis in CCR2- and CCR5-deficient mice by continuous oral administration of dextran sodium sulfate (DSS). Both CCR2- and CCR5-deficient mice were susceptible to DSS-induced intestinal inflammation. The lack of CCR2 or CCR5 did not reduce the DSS-induced migration of macrophages into the colonic lamina propria. However, both CCR5-deficient mice and, to a lesser degree, CCR2-deficient mice were protected from DSS-induced intestinal adhesions and mucosal ulcerations. CCR5-deficient mice were characterized by a greater relative infiltration of CD4+ and NK1.1+ lymphocyte in the colonic lamina propria when compared to wild-type and CCR2-deficient mice. In CCR5-deficient mice, mucosal mRNA expression of IL-4, IL-5, and IL-10 was increased, whereas that of IFN-gamma was decreased, corresponding to a Th2 pattern of T cell activation. In CCR2-deficient mice, the infiltration of Th2-type T cells in the lamina propria was absent, but increased levels of IL-10 and decreased levels of IFN-gamma may have down regulated mucosal inflammation. Our data indicate that CCR5 may be critical for the promotion of intestinal Th1-type immune responses in mice.

Animals↗

PubMed2000

Chronic murine colitis is dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154 administration.

BACKGROUND & AIMS: Experimental colitis in most animal models is caused by dysregulation of T lymphocytes that display a T helper 1 (Th1) phenotype. CD154 (CD40L/gp39), a member of the tumor necrosis factor (TNF) family, is up-regulated on T cells on activation and has been shown to play a key role in the induction of a Th1 response. We investigated whether chronic experimental colitis is dependent on the CD154/CD40 pathway and whether disease can be prevented by anti-CD154 antibody treatment. METHODS: Two models of chronic colitis were used: CD45Rb(hi) cell transfer into recombination activation gene-deficient (Rag(-/-)) mice and bone marrow transplant of tgepsilon26 animals. In both models, mice were reconstituted with cells from CD154-deficient animals. In another series of experiments, wild-type CD45Rb(hi) T cell-reconstituted recipients were treated with anti-CD154, either from the start of the experiment or after onset of disease. RESULTS: T cells deficient in CD154 induced a milder clinical disease, less weight loss, and fewer histologic signs of colitis than wild-type cells. The level of interleukin 12 in the serum of CD154-deficient T-cell recipients was 5-fold less than that of wild-type cell recipients. Nevertheless, no signs of deviation from a Th1 phenotype were observed. Treatment with anti-CD154 antibodies substantially impaired disease development, even when started after the onset of colitis. CONCLUSIONS: The CD154/CD40 pathway plays a critical role in Th1-induced chronic experimental colitis. Blocking CD154, even after the onset of disease, ameliorates colitis but does not induce a T helper 2 (Th2) phenotype.

Animals↗

PubMed2000

Limited CD4 T-cell diversity associated with colitis in T-cell receptor alpha mutant mice requires a T helper 2 environment.

BACKGROUND & AIMS: T-cell receptor alpha mutant (TCRalpha(-/-)) mice spontaneously develop chronic colitis mediated by CD4(+) TCRalpha(-)beta(+) T cells. The aim of this study was to analyze the mechanisms of expansion of these cells by characterization of the TCRbeta repertoire. METHODS: TCRbeta repertoire was analyzed by reverse-transcription polymerase chain reaction/Southern blot and DNA sequencing. Clonality of T cells was examined in the lymphoid tissues and colons of TCRalpha(-/-) mice and interleukin 4-deficient TCRalpha(-/-) mice. In addition, an in vitro culture system using syngeneic colonic epithelial cells as antigens was used. RESULTS: The clonal expansion of a restricted subset of Vbeta8.2(+) T cells was characterized by conservation of a single negatively charged amino acid residue in the second position of the complementarity-determining region 3 (CDR3). These T cells were observed in the diseased colon and appendix (cecal patch) of TCRalpha(-/-) mice, but not germfree TCRalpha(-/-) mice. Culture of polyclonal T cells from young TCRalpha(-/-) mice with colonic epithelial cells under T helper 2 conditions resulted in the survival of Vbeta8.2(+) T cells characterized by the same CDR3 pattern. In addition, the transfer of the cultivated T cells induced mild colitis in recombination-activating gene 1 mutant mice. CONCLUSIONS: In the TCRalpha(-/-) mice, the development of colitis is associated with the presence of a restricted diversity of Vbeta8. 2(+) T-cell subsets characterized by a specific TCR motif. The limited diversity of lamina propria T cells that are derived from naive T cells expanded by reacting with luminal bacterial antigens is likely caused by the survival of these T cells after stimulation with self-antigens in the presence of a T helper 2 environment.

Amino Acid Sequence↗

PubMed2000

Regulatory role of mature B cells in a murine model of inflammatory bowel disease.

The spontaneous chronic colitis in TCR alpha mutant (TCRalpha(-/-)) mice mediated by CD4(+) TCRalpha(-)beta(+) T cells is more severe in the absence of mature B cells, suggesting a suppressive role of B cells and Ig in the development of chronic colitis. To investigate the direct role of B cells in the suppression of this colitis, cell transfer studies were performed in TCRalpha(-/-) x Igmu(-/-) (alphamu(-/-)) double-knockout mice. The chronic colitis was markedly attenuated in alphamu(-/-) mice after the adoptive transfer of peripheral B cells from TCRalpha(-/-) mice into 3- to 4-week-old alphamu(-/-) mice prior to the development of colitis. Furthermore, transfer of mature B cells from TCRalpha(-/-) mice markedly decreased the number of pathogenic colonic CD4(+) TCRalpha(-)beta(+) T cells in alphamu(-/-) mice with established colitis. This B cell effect required the presence of functional co-stimulatory molecules CD40 and B7-2 (CD86) but not B7-1 (CD80). These results indicate that mature B cells play an important role in the development of chronic colitis in TCRalpha(-/-) mice by directly regulating the pathogenic T cells (CD4(+) TCRalpha(-)beta(+) T cells).

Adoptive Transfer↗

PubMed2000

Spontaneous chronic colitis in TCR alpha-mutant mice; an experimental model of human ulcerative colitis.

Mice with targeted disruption of the T cell receptor alpha gene (TCR alpha-/-) spontaneously develop chronic colitis. Colonic inflammation begins at 6-8 weeks of age and chronic colitis is established in about 60% of mice by 16-20 weeks of age. The disease is also associated with autoantibodies (anti-tropomyosin antibodies, anti-neutrophil cytoplasmic antibodies) and an oligoclonal immune response to luminal bacterial antigens. Although T cells, but not B cells or autoantibodies, are essential for the development of colitis, B cells and/or autoantibodies may have a regulatory role in the pathogenesis of this colitis because the colitis is more severe in B cell deficient TCR alpha-/- mice. Cytokines, specifically IL-4 and IL-1, also play an important role in the development of colitis in TCR alpha-/- mice. Enteric bacteria located in the large intestine are an important factor in the pathogenesis of this colitis because germ-free TCR alpha-/- mice do not develop colitis and appendectomy at an early age delays the onset of this colitis. The colitis in TCR alpha-/- mice resembles human ulcerative colitis and provides a useful model to study the pathogenesis of human inflammatory bowel disease.

Animals↗

PubMed1999

Regulation of human intestinal intraepithelial lymphocyte cytolytic function by biliary glycoprotein (CD66a).

Human small intestinal intraepithelial lymphocytes (iIEL) are a unique population of CD8alphabeta+ TCR-alphabeta+ but CD28- T lymphocytes that may function in intestinal epithelial cell immunosurveillance. In an attempt to define novel cell surface molecules involved in iIEL function, we raised several mAbs against activated iIELs derived from the small intestine that recognized an Ag on activated, but not resting, iIELs. Using expression cloning and binding studies with Fc fusion proteins and transfectants, the cognate Ag of these mAbs was identified as the N domain of biliary glycoprotein (CD66a), a carcinoembryonic Ag-related molecule that contains an immune receptor tyrosine-based inhibitory motif. Functionally, these mAbs inhibited the anti-CD3-directed and lymphokine-activated killer activity of the P815 cell line by iIELs derived from the human small intestine. These studies indicate that the expression of biliary glycoprotein on activated human iIELs and, potentially, other mucosal T lymphocytes is involved in the down-regulation of cytolytic function.

Animals↗

PubMed1999

High- and low-affinity single-peptide/MHC ligands have distinct effects on the development of mucosal CD8alphaalpha and CD8alphabeta T lymphocytes.

In this study, we compared the influence of two peptides on the selection of CD8alphaalpha and CD8alphabeta intraepithelial lymphocytes (IELs) of the intestine, which develop by a unique and partially thymus-independent process. Mice were used in which all T cells carried one transgenic T cell antigen receptor (TCR) (F5), and in which only well defined transgenic peptides were presented by H-2Db. The first peptide, for which the F5 TCR has a high affinity, derives from the influenza virus nucleoprotein (NP68). The second peptide, NP34, is an antagonistic variant of NP68 and is recognized by the F5 TCR with low affinity. To avoid presentation of endogenous peptides or production of T cells carrying alternative TCRs, F5 TCR transgenic mice were generated that were deficient for Tap-1 and Rag-1. In these mice, no CD3(+)CD8(+) cells were found in lymph nodes, spleen, or intestine. Introduction of transgenes encoding either NP34 or NP68 along with an endoplasmic reticulum signal sequence enabled Tap-1-independent expression of each peptide in these mice. Positive selection of F5TCR+CD8(+) thymocytes was not rescued by these transgenic peptides. However, the high-affinity NP68 peptide induced maturation of CD8alphaalpha IEL, whereas the low-affinity NP34 peptide stimulated development of both CD8alphabeta and CD8alphaalpha IEL, but in smaller numbers. When both peptides were present, CD8alphabeta T cells failed to develop and the number of CD8alphaalpha IELs was lower than in mice carrying the NP68 transgene alone. These data demonstrate that single ligands with a high or low affinity for TCR are capable of inducing or inhibiting the maturation of alternative subsets of IELs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

The critical role of interleukin 4 but not interferon gamma in the pathogenesis of colitis in T-cell receptor alpha mutant mice.

BACKGROUND & AIMS: T-cell receptor alpha mutant (TCRalpha-/-) mice spontaneously develop colitis resembling ulcerative colitis (UC). The role of interleukin (IL)-4 and interferon (IFN)-gamma in the pathogenesis of colitis was examined by creating IL-4- or IFN-gamma-deficient TCRalpha-/- mice. METHODS: Double-mutant mice were created by crossing TCRalpha-/- mice with IL-4- or IFN-gamma-deficient mice. Colitis was grossly and histologically assessed at 6 months of age, and the cytokine profile in the mesenteric lymph nodes and colons in these mice was analyzed. RESULTS: The lack of IL-4 dramatically suppressed the development of colitis at 6 months of age. In contrast, IFN-gamma-/- x TCRalpha-/- mice developed colitis similar to that present in TCRalpha-/- mice. Furthermore, proliferation of colonic epithelial cells was markedly increased in TCRalpha-/- mice and IFN-gamma-/- x TCRalpha-/- mice compared with IL-4(-/-) x TCRalpha-/- mice. Continuous administration of recombinant IL-4 led to increased colonic epithelial cell proliferation in IL-4(-/-) x TCRalpha-/- mice. CONCLUSIONS: IL-4 plays an important role in the development of colitis in TCRalpha-/- mice. In contrast, severe colitis in TCRalpha-/- mice can develop in the absence of IFN-gamma.

Animals↗

PubMed1999

Lessons for human inflammatory bowel disease from experimental models.

Experiments carried out in new rodent models of chronic intestinal inflammation provide important clues about the pathogenesis of human inflammatory bowel disease (IBD). Genetic factors and enteric microflora are driving forces regulating mucosal immune responses, some of which are pathogenic and lead to colitis. CD4(+) T cells are the major pathogenic cells in colitis, and the type of injury depends on the nature of the cytokine imbalance. The cytokine network controlled by CD4(+) T cells dictates the outcome of the mucosal immune responses. Certain cytokines, such as transforming growth factor-beta and interleukin-10, have a suppressive role, and immunoregulatory T cells capable of secreting these cytokines may be induced at intestinal mucosal sites. Lessons learned from these experimental models are leading to new strategies for the treatment of IBD.

Journal Article↗

PubMed1999

Colitis in transgenic and knockout animals as models of human inflammatory bowel disease.

Spontaneous colitis in knockout (KO) and transgenic rodents provides experimental models to study the development of mucosal inflammation and inflammatory bowel disease (Crohn's disease and ulcerative colitis). Genetic and environmental factors, particularly the normal enteric flora, are important factors in the development of mucosal inflammation. The normal mucosal homeostasis is disrupted when there is either cytokine imbalance, abrogation of oral tolerance, alteration of epithelial barrier and function or loss of immunoregulatory cells. Some but not all immunodeficiencies, in the appropriate setting, lead to colitis. CD4+ T cells have been identified as the pathogenic T cells in colitis, which mediate inflammation by either the Th1 or the Th2 pathway. The Th1 pathway dominates most colitis models and in Crohn's disease. In contrast, the colitis in TCR alpha KO mice shares many features of ulcerative colitis including the dominance of Th2 pathway in colonic inflammation. A major benefit of these models is in the development of therapeutic strategies for the treatment of inflammatory bowel disease.

Animals↗

PubMed1999

Roles of TH1 and TH2 cytokines in a murine model of allergic dermatitis.

Skin lesions in atopic dermatitis (AD) are characterized by hypertrophy of the dermis and epidermis, infiltration by T cells and eosinophils, and expression of the cytokines IL-4, IL-5, and IFN-gamma. The role of these cytokines in the pathogenesis of AD is not known. We took advantage of a recently described murine model of AD elicited by epicutaneous sensitization with ovalbumin (OVA) (1) and of the availability of mice with targeted deletions of the IL-4, IL-5, and IFN-gamma cytokine genes to assess the role of these cytokines in this model.OVA-sensitized skin from IL-5(-/-) mice had no detectable eosinophils and exhibited decreased epidermal and dermal thickening. Sensitized skin from IL-4(-/-) mice displayed normal thickening of the skin layers but had a drastic reduction in eosinophils and a significant increase in infiltrating T cells. These findings were associated with a reduction in eotaxin mRNA and an increase in mRNA for the T-cell chemokines macrophage inflammatory protein-2 (MIP-2), MIP-1beta, and RANTES. Sensitized skin from IFN-gamma-/- mice was characterized by reduced dermal thickening. These results suggest that both the TH2 cytokines IL-4 and IL-5 and the TH1 cytokine IFN-gamma play important roles in the inflammation and hypertrophy of the skin in AD.

Allergens↗

PubMed1998

Inhibition of intrathymic T cell development by expression of a transgenic antagonist peptide.

The mature T cell receptor (TCR) repertoire is shaped by positive- and negative-selection events taking place during T cell development. These events are regulated by interactions between the TCR and major histocompatibility complex molecules presenting self-peptides. It has been shown that many antagonist peptides are efficient at mediating positive selection. In this study we analyzed the effects of a transgene encoding an antagonist peptide (influenza NP34) that is presented by H-2Db in a Tap-1-independent fashion in mice expressing the influenza NP68-specific TCR F5. We find that the transgenic peptide does not mediate positive or negative selection in F5(+)Tap-1(-/-) mice, but inhibits maturation of CD8(+) single positive thymocytes in F5(+)Tap-1(+) mice without inducing signs of negative selection. We conclude that antagonism of antigen recognition occurs not only at the level of mature T cells but also in T cell development.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/Signal transducer and activator of transcription (Stat)-4 pathway, but is not conditional on interferon gamma expression by T cells.

The requirements for interleukin (IL)-12/signal transducer and activator of transcription (Stat)-4 signaling and induction of T cell-specific interferon (IFN)-gamma expression in the development of T helper cell (Th)1-type pathology were examined in two different models of experimental colitis. In each model, abnormal reconstitution of the T cell compartment in immunodeficient mice by adoptive cell transfer leads to a wasting syndrome and inflammation of the colon, induced by IFN-gamma and tumor necrosis factor (TNF)-alpha-producing T cells. We show here that treatment with anti-IL-12 antibodies in one of the models, or reconstitution with T cells from Stat-4-deficient (Stat-4(null)) mice in both models resulted in a milder disease in the majority of recipient animals, compared with those that were left untreated or that had been reconstituted with wt cells. Protected mice in each group also harbored lower frequencies of IFN-gamma-producing T cells than did diseased mice, suggesting that effects on wasting and colitis resulted from the attenuation of IFN-gamma expression by T cells. To test whether the development of pathogenic T cells in the two colitis models was directly dependent on T cell-specific IFN-gamma expression, IFN-gammanull donors were used for T cell reconstitution in each system. Surprisingly, large numbers of IFN-gammanull-reconstituted mice developed wasting and colitis, which in many cases was of comparable severity to that seen in animals reconstituted with wt cells. Furthermore, T cells from these animals expressed TNF-alpha, demonstrating that they had retained the ability to produce another proinflammatory cytokine. Taken together, these results demonstrate that in some forms of chronic experimental colitis the development of pathogenic T cells is influenced predominantly, though not exclusively, by IL-12 via the actions of Stat-4 proteins. Furthermore, our data suggest that in the models of colitis studied here the effects of IL-12/Stat-4 or other Th1 promoting pathways are not limited to the induction of IFN-gamma gene expression in T lymphocytes.

Animals↗