A cytokine-to-chemokine axis between T lymphocytes and keratinocytes can favor Th1 cell accumulation in chronic inflammatory skin diseases

The recruitment of T cells into the skin is regulated by chemokines released by resident cells. In this study, we found that normal human keratinocytes activated with Th1-derived supernatant (sup) expressed early (6-12 h) IP-10/CXCL10, MCP-1/CCL2, IL-8/CXCL8, and I-309/CCL1 mRNAs and with slower kinetics (24-96 h), RANTES/CCL5 and MDC/CCL22 mRNAs. Upon stimulation with the Th1 sup, keratinocytes secreted high levels of RANTES, IP-10, MCP-1, and IL-8 and moderate levels of I-309 and MDC. Although much less efficiently, Th2 sup could also induce keratinocyte expression of IL-8, IP-10, RANTES, and MCP-1 but not of I-309 and MDC. TARC/CCL17 was not significantly induced by any stimuli. Sup from keratinocytes activated with Th1-derived cytokines elicited a strong migratory response of Th1 cells and a limited migration of Th2 cells, whereas sup from Th2-activated keratinocytes promoted a moderate migration of Th1 and Th2 lymphocytes. Thus, keratinocytes appear considerably more sensitive to Th1- than to Th2-derived lymphokines in terms of chemokine release and can support the preferential accumulation of Th1 lymphocytes in the skin.     

Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine

Helper T cells are classified into Th1 and Th2 subsets based on their profiles of cytokine production. Th1 cells are involved in cell-mediated immunity, whereas Th2 cells induce humoral responses. Selective recruitment of these two subsets depends on specific adhesion molecules and specific chemoattractants. Here, we demonstrate that the T cell-directed CC chemokine thymus and activation-regulated chemokine (TARC) was abundantly produced by monocytes treated with granulocyte macrophage colony stimulating factor (GM-CSF) or IL-3, especially in the presence of IL-4 and by dendritic cells derived from monocytes cultured with GM-CSF + IL-4. The receptor for TARC and another macrophage/dendritic cell-derived CC chemokine macrophage-derived chemokine (MDC) is CCR4, a G protein-coupled receptor. CCR4 was found to be expressed on approximately 20% of adult peripheral blood effector/memory CD4+ T cells. T cells attracted by TARC and MDC generated cell lines predominantly producing Th2-type cytokines, IL-4 and IL-5. Fractionated CCR4+ cells but not CCR4- cells also selectively gave rise to Th2-type cell lines. When naive CD4+ T cells from adult peripheral blood were polarized in vitro, Th2-type cells selectively expressed CCR4 and vigorously migrated toward TARC and MDC. Taken together, CCR4 is selectively expressed on Th2-type T cells and antigen-presenting cells may recruit Th2 cells expressing CCR4 by producing TARC and MDC in Th2-dominant conditions.     

The assignment of chemokine-chemokine receptor pairs: TARC and MIP-1 beta are not ligands for human CC-chemokine receptor 8.

Identification of chemokine receptors and their associated ligands is crucial to the understanding of most immune reactions. Three human chemokines [I-309, thymus and activation-regulated chemokine (TARC) and macrophage inflammatory protein-1beta (MIP-1beta)] have been reported to be ligands for CC-chemokine receptor 8 (CCR8). In this report, we present evidence that TARC and MIP-1beta did not bind to or induce chemotaxis through CCR8 on a stable transfected cell line (1D-21) and did not bind to CCR8 on in vitro differentiated human CD4(+) Th(2) cell cultures. Also, I-309-dependent calcium mobilization in 1D-21 cells and in Th(2) cells was desensitized by I-309 but not by MIP-1beta or TARC. These results provide strong evidence that, at physiologically relevant concentrations, I-309 is the only known human ligand for CCR8. These data also provide a framework for suggesting minimum requirements for the assignment of chemokine receptor-ligand pairs.     

Skewing of cytotoxic activity and chemokine production,but not of chemokine receptor expression,in human type-1/-2 gamma delta T lymphocytes

Human Vgamma9/Vdelta2(+) T lymphocytes participate in the immune response against intracellular pathogens through the secretion of type-1 cytokines and chemokines and by killing of infected cells. Little is known of the effects by type-2 differentiation of gamma delta cells on these functions. Here, we report that bona fide naive cord blood-derived gamma delta lymphocytes expanded in vitro with the mycobacterial antigen isopentenyl pyrophosphate (IPP) can be differentiated as either type-1 or type-2 cells, in the presence of an appropriate cytokine milieu. Instead, peripheral gamma delta cells from PPD-negative healthy adults displayed a type-1 cytokine profile, i.e. IPP-stimulated secretion of IFN-gamma, but not of IL-4 and IL-10. Moreover, they released the macrophage inflammatory protein (MIP)-1beta, but not IL-8 nor the Th2 chemoattractants I-309 and TARC (thymus and activation-regulated chemokine). This cytokine profile was not significantly affected by in vitro culture in Th2 polarizing conditions. Only in one case out of seven were peripheral gamma delta cells fully differentiated to type-2 lymphocytes, characterized by sustained IL-4 and IL-10 production, along with secretion of substantial amounts of IL-8, I-309 and TARC. Type-2 gamma delta T lymphocytes preferentially expressed the co-stimulatory molecule CD30; conversely, no skewing in chemokine receptor expression was observed. Both polarized populations displayed high levels of CXCR3 in the absence of CCR3, CCR4 and CCR5. Finally, type-1, but not type-2, gamma delta T lymphocytes killed IPP-pulsed U937 cells and displayed elevated perforin content. Overall, our data suggest that type-2 differentiation of gamma delta T lymphocytes profoundly affects both their effector functions and their potential to recruit the appropriate leukocyte subsets to the sites of inflammation.     

Chemokines, chemokine receptors and allergy

Chemokines are a group of cytokines that are responsible for the influx of blood cells, including T and B lymphocytes, monocytes, neutrophils, eosinophils and basophils, in allergic and other inflammatory conditions. They function as G protein-coupled chemotactic factors which also activate the cells with which they interact. Certain chemokines function within the afferent arm of the immune system, in which antigen is processed and antibody formation initiated, and others are active within the effector pathways of cellular immunity and late-phase allergic reactions. Th2 lymphocytes, which are critical for allergy, employ the CC chemokine receptors CCR4 and CCR8 with the ligands thymus- and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and I-309, respectively. The chemokine receptor CCR3 and ligands monocyte chemoattractant protein (MCP)-3, MCP-4, regulated upon activation normal T cell expressed and secreted (RANTES) and eotaxins I and II are of particular relevance for the recruitment and activation of eosinophils. Th1 reactions depend upon interferon gamma-induced CXC chemokines interferon- inducible protein (IP)-10, interferon-inducible T cell-alpha chemoattractant (iTAC) and monokine induced by interferon-gamma (MiG), which bind to chemokine receptor CXCR3.     

Release of both CCR4-active and CXCR3-active chemokines during human allergic pulmonary late-phase reactions

BACKGROUND: Segmental antigen bronchoprovocation has long been used as a model to study allergic pulmonary inflammatory responses. Among the characteristics of the resulting cellular infiltrate is the preferential recruitment of TH2 lymphocytes. The mechanisms responsible for their selective recruitment remain unknown, but T(H)(2) cells preferentially express the chemokine receptors CCR4 and CCR8. OBJECTIVES: We tested the hypothesis that the chemokines thymus- and activation-regulated chemokine (TARC) (CCL17) and macrophage-derived chemokine (MDC) (CCL22), whose receptor is CCR4, and I-309 (CCL1), whose receptor is CCR8, would be released at sites of segmental allergen challenge. METHODS: Segmental allergen challenge with saline or allergen was performed in 10 adult allergic subjects with asthma, who were off medications. Bronchoalveolar lavage (BAL) was performed at both the saline- and allergen-challenged sites 20 hours after challenge. BAL fluids were analyzed for total cell counts and differentials, and supernatants were assayed by ELISA for levels of TARC, MDC, and I-309. As a control, the BAL fluids were also analyzed for levels of interferon-inducible protein 10 (IP-10) (CXCL10), an IFN-gamma-induced chemokine active on CXCR3, a chemokine receptor that is preferentially expressed on TH1 lymphocytes. RESULTS: Allergen challenge led to an approximately 6-fold increase in total leukocytes, including lymphocytes, compared with those seen at saline-challenged sites. At antigen-challenged sites, eosinophils predominated. Chemokine levels at control, saline-challenged sites were either below the detectable limit or low, with the predominant chemokine detected being IP-10. At antigen-challenged sites, levels of MDC, TARC, and IP-10 were all significantly increased compared with saline sites, each with a median of 486 to 1130 pg/mL detected. On the basis of a comparison with serum values, BAL chemokine levels at most antigen-challenged sites could not be accounted for by transudation from plasma. In contrast, levels of I-309 were extremely low or undetectable in all BAL and serum samples tested. Finally, BAL levels of MDC significantly correlated with those for TARC, but no significant correlations were found between levels of chemokine and any cell type. CONCLUSIONS: These data suggest that among the chemokines measured in this study, IP-10 is the predominant chemokine detected 20 hours after saline challenge, likely representing baseline production of a chemokine that favors TH1 cell recruitment. At antigen-challenged sites, levels of both CCR4 and CXCR3 active chemokines, but not CCR8 active chemokines, are markedly increased and are produced at levels that are likely to have biologic significance. Given the preferential accumulation of TH2 cells at these antigen-challenged sites, the increased production of CCR4-active chemokines might contribute to this response.     

Cytokine/chemokine profiles contribute to understanding the pathogenesis and diagnosis of primary Sjögren's syndrome

To investigate the pathogenesis of localized autoimmune damage in Sjögren's syndrome (SS) by examining the expression patterns of cytokines, chemokines and chemokine receptors at sites of autoimmune damage. mRNA expression of these molecules in the labial salivary glands (LSGs) and peripheral blood mononuclear cells (PBMCs) from 36 SS patients was examined using a real‐time polymerase chain reaction‐based method. Subsets of the infiltrating lymphocytes and chemokines/chemokine receptors expression in the LSG specimens were examined by immunohistochemistry. Cytokines/chemokine concentrations in the saliva were analysed using flow cytometry or enzyme‐linked immunosorbent assay. mRNA expression of T helper type 1 (Th1) cytokines, chemokines and chemokine receptors was higher in LSGs than in PBMCs. In contrast, mRNA expression of Th2 cytokines, chemokines [thymus and activation‐regulated chemokine (TARC/CCL17), macrophage‐derived chemokine (MDC/CCL22)] and chemokine receptor (CCR4) was associated closely with strong lymphocytic accumulation in LSGs. Furthermore, TARC and MDC were detected immunohistochemically in/around the ductal epithelial cells in LSGs, whereas CCR4 was detected on infiltrating lymphocytes. The concentrations of these cytokines/chemokines were significantly higher in the saliva from SS patients than those from controls, and the concentrations of Th2 cytokines/chemokines were associated closely with strong lymphocytic accumulation in LSGs. These results suggest that SS might be initiated and/or maintained by Th1 and Th17 cells and progress in association with Th2 cells via the interaction between particular chemokines/chemokine receptors. Furthermore, the measurement of cytokines/chemokines in saliva is suggested to be useful for diagnosis and also to reveal disease status.     

Pulmonary chemokines and their receptors differentiate children with asthma and chronic cough

BACKGROUND: Cough is a frequent symptom in children, but the differentiation of asthmatic cough from cough of other origins can be difficult. Chemokines recruit T lymphocytes to inflamed tissues, and the corresponding chemokine receptors are differentially expressed on T H 1 and T H 2 cells. OBJECTIVE: We sought to determine whether levels of T H 1/T H 2-related chemokines and their receptors differ in bronchoalveolar lavage fluid (BALF) from 12 children with allergic asthma, 15 nonatopic children with chronic cough, and 10 children without airway disease. METHODS: The T H 1-related (IFN-gamma-inducible protein of 10 kd [IP-10], IFN-gamma-inducible T cell alpha chemoattractant [ITAC], monokine induced by IFN-gamma [Mig], and IFN-gamma) and T H 2-related (thymus- and activation-regulated chemokine [TARC], macrophage-derived chemokine [MDC], IL-5, and IL-4) chemokines and cytokines were quantified in BALF by ELISA and a particle-based multiplex array. Percentages of pulmonary lymphocytes expressing CXCR3 + and CCR5 + (T H 1) and CCR4 + and CCR3 + (T H 2) chemokine receptors were determined in BALF by flow cytometry. RESULTS: Pulmonary CCR4 + CD4 + cells and levels of TARC and MDC were significantly increased in asthmatic children versus children with chronic cough or without airway disease. In asthmatic children CCR4 + CD4 + cells correlated positively with levels of TARC, MDC, and serum IgE levels and negatively with FEV 1 . In contrast, CXCR3 + CD8 + cells and levels of ITAC were significantly increased in children with non-atopic chronic cough compared with the other groups. In children with chronic cough, CXCR3 + CD8 + cells correlated with levels of ITAC and IFN-gamma. CONCLUSION: Pulmonary CCR4 + CD4 + and CXCR3 + CD8 + cells and their ligands TARC, MDC, and ITAC clearly differentiate asthmatic children from nonatopic children with chronic cough. The analysis of these markers could facilitate the diagnostic discrimination of asthma versus other reasons for chronic cough in children.     

Cytokines and chemoattractants in allergic inflammation

It is now generally accepted type 2 T helper (Th2) cytokines and some chemoattractants play an essential role in the pathogenesis of the allergic inflammation. The effects of Th2 cytokines, such as interleukin (IL)-4, IL-5, IL-9, and IL-13, account for virtually all the pathophysiological manifestations of allergy and asthma. Moreover, both Th2 cells and the effector cells usually present in the areas of allergic inflammation (basophils, mast cells, and eosinophils) express chemoattractant receptors, such as CCR3, CCR4, CCR8 and CRTH2. Therefore, interactions of eotaxin(s), eotaxin/CCL11, RANTES/CCL5, and MCP-1/CCL2, MCP-2/CCL8, MCP-3/CCL7, MCP-4/CCL13 with CCR3 are responsible for the recruitment of basophils, eosinophils and mast cells, whereas interactions of CCR4 with MDC/CCL22 or TARC/CCL17, CCR8 with I-309/CCL1, and CRTH2 with prostaglandin D(2) play a critical role in the allergen-induced recruitment of Th2 cells in the target tissues of allergic inflammation. The demonstration that Th2-polarized responses against allergens represent the triggering event for the development of allergic diseases, together with the recognition that some chemoattractants are responsible for the recruitment of both Th2 cells and other effector cells of allergic inflammation, can provide the conceptual basis for the development of new therapeutic strategies in allergic conditions.     

CpG-ODN inhibits airway inflammation at effector phase through down-regulation of antigen-specific Th2-cell migration into lung

Allergic airway inflammation is one of the most typical characteristic features of bronchial asthma. T(h)2 cells, which produce IL-4, IL-5 and IL-13, are well known as major effector lymphocytes of the inflammation. In the present work, we found that subcutaneous injection of Toll-like receptor-9-ligand, CpG-oligodeoxynucleotides (CpG-ODN), remarkably suppressed eosinophilia and mucus hyper-production in T(h)2 cell-dependent airway inflammation model at the effector phase. The injection of CpG-ODN significantly blocked T(h)2 cell migration into lung. The inhibitory effects of CpG-ODN were observed even when IFN-gamma-deficient T(h)2 cells were transferred into IFN-gamma(-/-) mice. In contrast, the administration of neutralizing mAbs against type I cytokines such as IFN-alpha, IFN-beta and IL-12 significantly suppressed the inhibitory effect of CpG-ODN on airway inflammation and T(h)2 cell migration into the lung. We further demonstrated that the production of T(h)2 chemokines, thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), was significantly reduced by the CpG-ODN. The reduction of both TARC and MDC was also inhibited by the blockade of IFN-alpha, IFN-beta and IL-12 with mAbs. Thus, we revealed here that IFN-alpha, IFN-beta and IL-12, but not IFN-gamma, were required for the inhibitory effect of CpG-ODN in T(h)2 cell-mediated allergic airway inflammation. The present evidence strongly suggest that induction of type I cytokines would be promising therapeutic targets in T(h)2-dependent allergic diseases such as bronchial asthma.     

Characterization of chemokines and chemokine receptors in two murine models of inflammatory bowel disease: IL-10-/- mice and Rag-2-/- mice reconstituted with CD4+CD45RBhigh T cells

We used quantitative PCR to investigate the expression of chemokines and chemokine receptors in two Th1-mediated murine models of inflammatory bowel disease (IBD). First, mRNA levels encoding the chemokines MIG, RANTES, lymphotactin, MIP-3alpha, TCA-3, TARC, MIP-3beta, LIX, MCP-1 and MIP-1beta and the receptors CCR4, CCR6 and CCR2 were significantly increased in chronically inflamed colons of IL-10-/- mice when compared with wildtype mice. Interestingly, reversal of colitis in IL-10-/- mice by anti-IL-12 mAb was accompanied by the inhibition in the expression of LIX, lymphotactin, MCP-1, MIG, MIP-3alpha, MIP-3beta, TCA-3, CCR2 and CCR4, whereas the increased mRNA levels of MIP-1beta, RANTES, TARC and CCR6 were unaffected. Second, to investigate which chemokines and receptors were up-regulated during the inductive phase of colitis, we employed the CD4+CD45RBhigh T cell transfer model. At 4 and 8 weeks after reconstitution of Rag-2-/- mice the mRNA levels of IP-10, MCP-1, MDC, MIG, TARC, RANTES, CCR4 and CCR5 were significantly increased prior to the appearance of macroscopic lesions. Other chemokines and chemokine receptors were clearly associated with the acute phase of the disease when lesions were evident. The sum of our studies with these two models identifies chemokines that are expressed at constant levels, irrespective of inflammatory responses, and those that are specifically associated with acute and/or chronic stages of Th1-driven colitis.     

Accumulation of CCR4-expressing CD4+ T cells and high concentration of its ligands (TARC and MDC) in bronchoalveolar lavage fluid of patients with eosinophilic pneumonia

BACKGROUND: Th2 cells are thought to be involved in eosinophilic inflammation of the lung. CC chemokine receptor 4 (CCR4) has been identified as a specific receptor for both thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), and is preferentially expressed on Th2 cells. OBJECTIVE: Our aim was to evaluate the role of Th2 cells in the lung of patients with eosinophilic pneumonia (EP). METHODS: The concentrations of TARC, MDC, and interleukin (IL)-5 were measured in bronchoalveolar lavage fluid (BALF) by ELISA. Proportion of CCR4-expressing CD4+ T cells (CCR4+ CD4+ T cells) was determined by flow cytometry. RESULTS: TARC and MDC concentrations in BALF were higher in patients with EP than in normal subjects. The proportion of CCR4-expressing cells among CD4+ T cells was higher in BALF than in peripheral blood of patients with EP. There was a significant correlation between the number of CCR4+ CD4+ T cells and the levels of TARC, MDC, and IL-5 in BALF of patients with EP. CONCLUSIONS: Our data suggest that Th2 cells, which express CCR4 and its ligands (TARC and MDC), contribute to the pathogenesis of EP in the lung.     

Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells.

When naive T lymphocytes are activated and differentiate into memory/effector cells, they down-regulate receptors for constitutive chemokines such as CXCR4 and CCR7 and acquire receptors for inflammatory chemokines such as CCR3, CCR5 and CXCR3, depending on the Th1/Th2 polarization. This switch in chemokine receptor usage leads to the acquisition of the capacity to migrate into inflamed tissues. Using RNase protection assays, staining with specific antibodies, and response to recombinant chemokines, we now show that following TCR stimulation, memory/effector T cells undergo a further and transient switch in receptor expression. CCR1, CCR2, CCR3, CCR5, CCR6 and CXCR3 are down-regulated within 6 h, while CCR7, CCR4, CCR8 and CXCR5 are up-regulated for 2 to 3 days. Up-regulation of CCR7 following TCR stimulation was observed also among resting peripheral blood T cells and required neither co-stimulation nor exogenous IL-2. On the other hand IL-2 down-regulated CXCR5, up-regulated CCR8 and facilitated the recovery of CCR3 and CCR5. Upon TCR stimulation, Th1 and Th2 cells produced comparable sets of chemokines, including RANTES, macrophage inflammatory protein-1beta, I-309, IL-8 and macrophage-derived chemokine, which may modulate surface chemokine receptors and contribute to cell recruitment at sites of antigenic recognition. Altogether these results show that following TCR stimulation effector/memory T cells transiently acquire responsiveness to constitutive chemokines. As a result, T cells that are activated in tissues may either recirculate to draining lymph nodes or migrate to nearby sites of organized ectopic lymphoid tissues.     

Distinct patterns and kinetics of chemokine production regulate dendritic cell function.

Dendritic cells (DC) have been showed to both produce and respond to chemokines. To understand how this may impact on DC function, we analyzed the kinetics of chemokine production and responsiveness during DC maturation. After stimulation with LPS, TNF-alpha or CD40 ligand, the inflammatory chemokines MIP-1alpha, MIP-1beta and IL-8 were produced rapidly and at high levels, but only for a few hours, while RANTES and MCP-1 were produced in a sustained fashion. The constitutive chemokines TARC, MDC and PARC were expressed in immature DC and were up-regulated following maturation, while ELC was produced only at late time points. Activated macrophages produced a similar spectrum of chemokines, but did not produce TARC and ELC. In maturing DC chemokine production had different impact on chemokine receptor function. While CCR1 and CCR5 were down-regulated by endogenous or exogenous chemokines, CCR7 levels gradually increased in maturing DC and showed a striking resistance to ligand-induced down-regulation, explaining how DC can sustain the response to SLC and ELC throughout the maturation process. The time-ordered production of inflammatory and constitutive chemokines provides DC with the capacity to self-regulate their migratory behavior as well as to recruit other cells for the afferent and efferent limb of the immune response.     

Maturation of human monocyte-derived dendritic cells (MoDCs) in the presence of prostaglandin E2 optimizes CD4 and CD8 T cell-mediated responses to protein antigens: role of PGE2 in chemokine and cytokine expression by MoDCs

Prostaglandin E2 (PGE2) acts in synergy with other inflammatory stimuli such as tumor necrosis factor (TNF) to induce the maturation of migratory-type monocyte-derived dendritic cells (MoDCs). However, PGE2 has been reported to inhibit IL-12p70 production by MoDCs and to promote the generation of Th2 T cell responses. We demonstrate here that the addition of PGE2 to TNF for the maturation of MoDCs enhanced CD4 and CD8 T cell proliferative responses to neoantigen and recall antigen, and enhanced Th1-type responses. The increased stimulatory capacity of MoDCs matured with PGE2 was associated with a fully mature, migratory-type MoDC phenotype and more rapid down-regulation of the expression of inflammatory chemokines, with up-regulated expression of the constitutive chemokines TARC and MDC. In addition, although MoDCs matured with TNF and PGE2 selectively produced the inhibitory IL-12p40 subunit at steady state, they were able to produce the bioactive IL-12p70 heterodimer after stimulation with CD40 ligand and/or IFN-gamma. Despite increased IL-6 mRNA expression, MoDCs matured with PGE2 did not overcome the suppressive effects of CD4+ CD25+ T cells in allogeneic mixed lymphocyte reactions. In conclusion, MoDCs matured in the presence of PGE2 display characteristics of more efficient antigen-presenting cells that might be optimal for use in cancer vaccine-based clinical trials.     

Regulated production of the T helper 2-type T-cell chemoattractant TARC by human bronchial epithelial cells in vitro and in human lung xenografts

The chemokine TARC is a ligand for the chemokine receptor CCR4 expressed on T helper (Th)2-type CD4 T cells. Allergic airway inflammation is characterized by a local increase in cells secreting Th2-type cytokines. We hypothesized that bronchial epithelial cells may be a source of chemokines known to chemoattract Th2 cells. Regulated TARC expression was studied using normal human bronchial epithelial cells and a human lung xenograft model. TARC expression was increased in normal human bronchial epithelial cells in response to tumor necrosis factor-alpha stimulation, and further upregulation of TARC was observed with interferon (IFN)-gamma but not interleukin (IL)-4 costimulation. TARC functions as a nuclear factor (NF)-kappa B target gene, as shown by the abrogation of TARC expression in response to proinflammatory stimuli when NF-kappa B activation is inhibited. In an in vivo model, minimal constitutive TARC expression was observed in human lung xenografts. Consistent with our findings in vitro, TARC messenger RNA (mRNA) expression was upregulated in the xenografts in response to IL-1, and costimulation with IFN-gamma but not IL-4 further increased TARC mRNA and protein expression. In addition, bronchoalveolar lavage fluid from asthmatic subjects after allergen challenge contained significantly increased levels of TARC, suggesting that TARC production by bronchial epithelial cells may play a role in the pathogenesis of allergic asthma.