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RESEARCH COMMUNICATION |
over IL-4 responses
a Department of Immunology, The University of Manitoba, Winnipeg, Canada
b Department of Pediatrics and Child Health, The University of Manitoba, Winnipeg, Canada
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUMMARYREFERENCES |
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(IFN-) and interleukin 4 (IL-4) production by fresh peripheral blood mononuclear cells. We demonstrate for the first time that this CXC chemokine selectively up-regulates human T cell cytokine synthesis, with enhancement selectively targeted to promotion of Th1-like dominance. Superantigen (TSST-1), soluble anti-CD3 mAb, and phytohemagglutinin were used to activate distinct intracellular signaling pathways, thereby inducing quantitatively different IFN-:IL-4 ratios. Selective enhancement of IFN- responses was consistently observed, with median increases of 105–470%. Environmental antigens (Ag) were used to evaluate IP-10's effect on CD4-dependent, chloroquine-sensitive cytokine synthesis. Ag-driven IFN- responses exhibited median 19- to 30-fold increases in the presence of nanomolar concentrations of rhIP-10. IL-4 responses were neither enhanced nor inhibited under any of the conditions tested. These findings suggest a potential role for this T cell-focused chemokine in maintenance of the default Th1-like responses usually seen to environmental Ag and indicate a potential application in the modulation of Ag-driven responses in vivo.—Gangur, V., Simons, F. E. R., HayGlass, K. T. Human IP-10 selectively promotes dominance of polyclonally activated and environmental antigen-driven IFN- over IL-4 responses. FASEB J. 12, 705–713 (1998)
Key Words: environmental antigens • Th1/Th2 subsets • chemokine • TNF • interleukin • interferon
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUMMARYREFERENCES |
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(IFN-)2 -inducible pro~tein 10 (IP-10), a member of the CXC or alpha subfamily of chemokines, was discovered a decade ago as a predominant cDNA expressed in recombinant (r) IFN--stimulated monocytic cell lines (4). It provided the first indication that chemokines are produced by cells other than platelets. Subsequently, IP-10 has been shown to be produced by a variety of cell types including keratinocytes, monocytes, neutrophils, lymphocytes, endothelial cells, and fibroblasts (reviewed in ref 5).
Although IP-10 was named as a protein inducible by IFN-, other agents including lipopolysaccharide, interleukin 1
(IL-1), IL-6, tumor necrosis factor (TNF-), IFN-, and IFN-ß induce IP-10 gene expression in vitro, with in vivo administration of TNF-, IFN-, or IL-12 in animal models being similarly effective (5). IFN- gene knockout mice express IP-10 mRNA, suggesting that IFN- is not absolutely necessary for in vivo IP-10 gene expression (6).
As with most chemokines, research has focused on the chemotactic properties of IP-10. It has recently been implicated in the induction of T cell [Ca2+]i fluxes and adhesion by modulating integrin conformation (7), monocyte chemotaxis (8), inhibition of endothelial cell proliferation (9) and angiogenesis (10, 11), inhibition of colony formation by hematopoietic progenitors (12), and chemotaxis and mobilization of intracellular calcium in natural killer cells (13), in addition to its effects on lymphocyte chemotaxis described initially (8, 14, 15).
IP-10 appears to differ from most CXC chemokines in that it has no activity on neutrophils (16) and targets lymphocytes specifically (5, 17). It binds to a heparin sulfate proteoglycan, a widely distributed, nonsignaling, cell surface structure (9), and to CXCR3, a recently cloned signaling receptor shared by IP-10, Mig, and I-TAC (17). CXCR3 mRNA is expressed in activated T cells and natural killer (NK) cells but not in monocytes, neutrophils, B cells, or a variety of immortalized cell lines (17). It was shown recently that the chemotactic activity of IP-10 in NK cells is coupled to G-proteins, although involvement of G-proteins in IP-10 action on T cells is unknown (13).
In view of the expanding list of biological activities discovered for chemokines, and for IP-10 in particular, we hypothesized that IP-10 may regulate immune responses not only by recruiting T cells to sites of inflammation, but also by modulating human cytokine synthesis patterns during the course of antigen (Ag) -driven responses. Specifically, we examined whether low levels of rIP-10 modulate IFN- and IL-4 responses elicited by polyclonal or exogenous antigen-driven stimulation. The data demonstrate that rIP-10 selectively activates and enhances antigen and mitogen-driven IFN- (but not IL-4) cytokine gene expression in vitro, which suggests a potential role for this widely expressed chemokine in the maintenance of the default Th1-dominated responses to environmental antigens usually observed in vivo.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUMMARYREFERENCES |
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Cell culture
Whole blood (25 ml) was collected into 1 ml of 2.7% EDTA. Peripheral blood mononuclear cells (PBMC) were obtained by centrifugation with Histopaque-1077 (Sigma, St. Louis, Mo.). Cells collected from the interface were washed twice in serum-free saline, counted (>99% viability as determined by trypan blue exclusion), and used for culture immediately or after storage in liquid nitrogen (viability, 90–98%). To avoid an excessively reductionist approach and in light of findings that CD8 and NK cells contribute to both cytokine and chemokine synthesis (18–20), unselected PBMC were used in this study in preference to rigorously purified CD4 T cells. Preliminary experiments were performed to determine the optimal culture conditions (cell number, day of harvest, antigen and polyclonal activator concentrations) to induce cytokine synthesis (data not shown). In the experiments presented, cells were cultured at a final concentration of either 1.5 and 2.5 x 106/ml for polyclonal and antigen-mediated activation, respectively, in 200 µl cultures set up in 96-well round bottom plates (Nunc, Roskilde, Denmark).
For each subject, cultures were prepared in the absence of stimuli as well as in the presence of rIP-10 alone (PeproTech, Rocky Hill, N.J., endotoxin 0.031 ng/mg); grass pollen extract (Hollister-Stier/Miles, Toronto, Ont.) at 400 µg/ml; Fel d 1 containing standardized cat hair extract at 500 BAU/ml (ALK SQ cat hair, Wallingford, Conn.); 1% phytohemagglutinin (PHA; Difco, Detroit, Mich.); soluble anti-CD3 mAb at 100 ng/ml (OKT3 purified from hybridomas obtained from the American Type Culture Collection, Rockville, Md.); or the superantigen toxic shock syndrome toxin 1 (TSST-1) (Sigma) at 10 ng/ml. To examine the effect of rIP-10 on polyclonal and Ag-driven responses, cultures were set up with and without these stimuli plus rIP-10 titrated over concentrations between 0.01 and 10 or, in some cases, 100 ng/ml. The same preparations of cat antigen (ALK SQ Cat Hair, ALK) and mixture of locally prevalent grass pollens (Hollister Stier/Miles, Toronto, Ont.) were used in vivo for epicutaneous testing and for in vitro culture. The rIP-10 used had maximal chemotactic activity, as measured by PeproTech on human monocytes in a modified Boyden chamber, at 50 ng/ml, indicative of a specific activity for this material comparable to that of preparations used by others (8). Experiments requiring neutralization of endogenous IFN- (see Results) used 1 µg/ml of neutralizing mouse anti-human IFN- Ab(Pharmingen, Mississauga, Ont.). This antibody (B27) has an ED50 for neutralization of >6 µg/ml rIFN- when used at 1 µg/ml. As negative control, normal mouse IgG (1 µg/ml, Sigma) was included in parallel cultures.
Cytokine assays
Cytokine levels were measured after duplicate titrations of four to eight dilutions falling on the linear part of the standard curve generated on each plate for the cytokine-specific, enzyme-linked immunoassays (ELISAs) used. The data presented represent means (±SEM) of quadruplicate determinations for each cytokine.
IL-2
An ELISA was established using paired antibodies from Pharmingen, with human rIL-2 as a standard in each assay. The sensitivity of the optimized ELISA was between 0.078 and 0.156 U/ml.
IL-4
Paired monoclonal antibodies (Pharmingen) were used to establish a highly sensitive ELISA. Recombinant human IL-4 standards of specific activity equivalent to that of WHO standard 88/656 (21) were included in each ELISA. The sensitivity of this assay was 0.9 to 1.9 pg/ml.
IFN-
An ELISA was carried out using pair mAb's obtained from Pharmingen. Internal standards of IFN- containing standard, calibrated against human IFN- reference reagent Gg23–901–530 (specific activity 7 x 105 U/mg, 1 NIH unit = 115 pg, provided by Dr. C. Laughlin, NIAID, Bethesda, Md.), were included in each ELISA. The lower limit of detection for the assay was typically 0.3 U/ml.
Proliferation assay
Fresh PBMC were isolated from healthy subjects and cultured at 1.5 x 106/ml without or with three different concentrations of cat (20, 100, and 500 U/ml) or grass antigen (100, 400, and 1600 µg/ml). The effect of rIP-10 on antigen-driven proliferation was examined by adding rIP-10 to these cultures at three different concentrations (10, 1, and 0.1 ng/ml). All cultures were prepared in duplicate. Cultures were pulsed with 1 µCi per well of [3H]thymidine on day 6 and cells were harvested 18 h later. The [3H]thymidine uptake was measured in a scintillation counter and expressed as dpm.
Statistical analysis
Significance was determined by using a nonparametric statistical test (Mann-Whitney U test).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUMMARYREFERENCES |
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synthesis but is without effect on IL-4 production
Fig. 1.
PHA, the most Th2-like polyclonal activator, induced the strongest IL-4 responses (median 14 pg/ml; range, 10–54 pg/ml; n=12 subjects), followed by soluble anti-CD3 mAb (median 2 pg/ml; range 2–11 pg/ml; n=12, Mann-Whitney vs. PHA P<0.00001) and TSST-1 (median 4.5 pg/ml; range, 2–8 pg/ml; n=8 P=0.0002). In contrast, TSST-1 elicited the most intense IFN- responses (median 269 U/ml, 203–1199 U/ml, n=8), followed by soluble anti-CD3 (median 75 U/ml, 10–696 U/ml, n=10, P=0.05) and PHA (median 38 U/ml, 22–90 U/ml, n=12, P=0.0002). Looked at as the ratio of IFN-:IL-4 synthesis, widely used as an approximation of the type 1 vs. type 2 balance, these polyclonal activators exhibit median ratios of 83, 41, and 8 for TSST-1, soluble anti-CD3, and PHA stimulation, respectively.
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These three polyclonal activators were used to evaluate the effect of rIP-10 on the expression of human cytokine synthesis patterns. As demonstrated in Fig. 2
for four subjects representative of the eight studied with TSST-1, IP-10 enhanced superantigen-driven IFN- production by 51–330% (median 235%, P<0.01 for all subjects). In marked contrast, exogenous IP-10 was without detectable effect on TSST-1-stimulated IL-4 synthesis. Similarly, IP-10 enhanced soluble anti-CD3 mAb-mediated IFN- (median increase, 470%; range, 59–800%), but consistently failed to affect IL-4 production at any concentrations tested in the 12 subjects examined. Finally, the effect of IP-10 on the most Th2-like activator, PHA, was examined. IFN- responses were elevated in each subject, with a median increase of 105% (range 25 to 347%). Indeed, PHA/IP-10-induced IFN- responses increased to the same range as those induced in response to the strongly Th1-like polyclonal activator anti-CD3 mAb (69–567 U/ml vs. 10–696 U/ml). As seen for the other polyclonal activators, rIP-10 had minimal impact on PHA-driven IL-4 synthesis, with responses ranging from 9 to 23 pg/ml without IP-10 vs. 11–32 pg/ml despite utilization of IP-10 at up to 100 ng/ml.
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Collectively, the results indicate that rIP-10, independent of the particular mode of polyclonal T cell activation used, selectively augments IFN- cytokine synthesis in vitro and fails to augment or inhibit IL-4 production. The concentration of rIP-10 eliciting maximal enhancement of IFN- synthesis fell between 0.1 and 1 ng/ml in most subjects, independent of the means of activation.
Substantially higher levels of rIP-10 (10–100 ng/ml) resulted in substantial induction of IFN- in three subjects (60, 95, and 195 U/ml) in the absence of deliberate T cell activation (data not shown). rIP-10 alone failed to induce IL-4 gene expression in any subjects under any condition tested (data not shown).
rIP-10 markedly enhances Th1- but not Th2-associated cytokine expression to environmental antigens
To better evaluate the role IP-10 might play in shaping cytokine synthesis within the context of physio~logically relevant immune responses, antigen-specific systems were used. Domestic cat and grass pollen antigens were selected because they are ubiquitous environmental antigens that commonly elicit cytokine responses in nonallergic subjects (22). As evident in Fig. 3,
both cat and grass antigens induced readily demonstrable IFN- synthesis in short-term primary culture. This cytokine synthesis was CD4 dependent, chloroquine sensitive, and blocked by the addition of purified anti-MHC class II antibodies (22; data not shown).
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Addition of low levels of rIP-10 (~0.1 ng/ml) markedly enhanced antigen-stimulated IFN- responses to both antigens (
Fig. 3). The median enhancement of cat antigen-driven IFN- was 30-fold whereas that seen in grass pollen-stimulated systems was 19-fold. Cultures without antigen exhibited IFN- below the limits of detection; those cultured with exogenous IP-10 (0.1 to 1.0 ng/ml) in the absence of antigen had IFN- levels ranging from undetectable to 4 U/ml in all but two instances.
Extensive titration experiments, shown in Fig. 4
for three subjects in cat antigen and three in grass pollen-dependent systems, examined the effect of rIP-10 over the range of 0.01 to 10 ng/ml. Data confirm the dose-dependent increase in environmental antigen-driven IFN- responses observed in the presence of IP-10.
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Only one of seven subjects expressed detectable IL-4 responses to cat and none expressed IL-4 to grass antigens ( Fig. 4). In marked contrast to its effect on environmental antigen-driven IFN- responses, the addition of exogenous rIP-10 of up to 10 ng/ml failed to induce or enhance either cat or grass antigen-driven IL-4 synthesis. Collectively, the results demonstrate the capability of IP-10 to selectively enhance IFN-, but not IL-4, gene expression in antigen-specific responses.
Because IFN- can inhibit IL-4 synthesis, we examined the possibility that the inability of rIP-10 to enhance antigen-driven IL-4 production was an indirect effect mediated by the high levels of IFN- produced in culture. However, in experiments performed in the presence of neutralizing anti-IFN- Ab at levels sufficient to neutralize in excess of 10,000 U/ml IFN- or with normal mouse IgG as a control, the effect of rIP-10 on IL-4 synthesis was not affected (data not shown). Together, the data argue that the failure of IP-10 to promote enhanced IL-4 levels is not secondary to the marked increases seen in IFN- synthesis.
rIP-10 is a potent inhibitor of antigen-driven proliferation of human PBMC
In view of these data suggesting that rIP-10 enhances antigen-driven recall IFN- responses, we examined whether this chemokine can act as a costimulator of Ag-driven T cell proliferation. Thus, the effect of rIP-10 was examined at three concentrations (10, 1, and 0.1 ng/ml) on cat and grass antigen-driven recall T cell proliferation, using PBMC from healthy subjects. All three subjects exhibited proliferative responses to both antigens at each concentration used in vitro ( Fig. 5).
However, in marked contrast to its effect on IFN- synthesis, human IP-10 exerted a dose-dependent inhibition of antigen-stimulated proliferative responses. The concentration of rIP-10 required to exert maximal inhibition of proliferation was generally 1 ng/ml, with median 30-fold inhibition in each case.
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Since rIP-10 inhibited proliferation while enhancing IFN- production, we addressed the possibility that this inhibition was an indirect effect resulting from the high levels of IFN- present in culture. Grass antigen-driven proliferation assays were prepared and the effect of rIP-10 was examined in the absence and presence of neutralizing anti-IFN- Ab. As a control, these assays were also carried out in the presence of an irrelevant normal mouse IgG. Figure 6
shows that rIP-10 inhibited antigen-driven proliferation to the same extent in the presence or absence of a 100-fold excess of neutralizing anti-IFN- Ab. These data suggest that rIP-10-mediated inhibition of proliferation was not dependent on the marked enhancement in IFN- synthesis.
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rIP-10 is a potent inhibitor of antigen-driven IL-2 production by human PBMC
Because IP-10 inhibited antigen-driven proliferation of PBMC in an IFN--independent manner, we examined the effect of this chemokine on antigen-driven IL-2 production. The effect of various concentrations of IP-10 (0.1, 1, and 10 ng/ml) on antigen-driven IL-2 production was examined in five subjects. rIP-10 inhibited IL-2 production in each, with a median inhibition of ~10-fold ( Fig. 7).
Along with the failure of neutralizing anti-IFN- Ab to restore IP-10-inhibited proliferative responses, this suggests that IP-10's inhibition of proliferation results from reduced IL-2 synthesis rather than excessive IFN-.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUMMARYREFERENCES |
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(a prototypic Th1-like cytokine) and IL-4 (prototypic Th2-like) cytokine synthesis was evaluated in response to three polyclonal activators that yield quantitatively distinct patterns of cytokine responses, ranging from those that are strongly Th1-like to one characterized by substantial Th2-associated activation (22). IP-10 selectively up-regulated polyclonally driven IFN- synthesis in each case but had no effect on induction, suppression, or enhancement on IL-4 synthesis. Recognizing that different means of T cell activation activate distinct intracellular signaling pathways (26) and that polyclonal vs. antigen-mediated stimulation may elicit qualitatively different cytokine gene expression patterns (22), we evaluated the effect of rIP-10 on conventional antigen-driven responses, finding the effect of IP-10 even more pronounced. rIP-10 strongly promoted IFN- synthesis, eliciting ~20- to 30-fold increases in the dominance of IFN- synthesis to two ubiquitous environmental antigens.
The enhancement of IFN- cytokine synthesis was due to a synergistic rather than an additive effect: although cat and grass antigens each induced low levels of IFN- by themselves (0.5 U/ml to 10 U/ml) in all subjects examined, the addition of rIP-10 led to enhancement of IFN- synthesis by manyfold relative to that of either antigen or IP-10 alone, arguing that it was acting as a costimulator of T cell activation. The concentration of rIP-10 used for these studies ranged from 0.01 to 100 ng/ml, with maximal effect on cytokine synthesis evident between 0.1 and 1 ng/ml. This is arguably within physiologically relevant levels, because 1) the levels of IP-10 production that are induced in rIFN--stimulated human PBMC in vitro range from ~40 to 60 ng/ml (27); 2) the dose of IP-10 required for inducing chemotaxis of, and calcium fluxes in, T cells falls in the range of 1–100 ng/ml (8); and 3) rIP-10 was shown to induce adhesion of T cells to extracellular matrix at 1 to 10 ng/ml (7). Thus, although IP-10 levels produced in vivo in response to antigen-mediated activation need to be defined, the impact of this chemokine in promoting preferential expression of Th1-associated patterns falls at the low end of the range used to study other biological activities of this chemokine. Indeed, a particularly striking observation was the low concentration of IP-10 that was effective—often as low as 1 pM. In contrast, many previously reported activities of IP-10, such as monocyte chemotaxis (8), chemotaxis of stimulated CD4 T cells (8), or adhesion of T cells to ICAM (7), are maximal at 10-to 500-fold higher concentrations (typically 10–50 ng/ml), in contrast to the 0.1 to 1.0 ng/ml used here.
We are unaware of previous reports examining the role of IP-10 or other CXC chemokines as modulators of cytokine synthesis patterns. A limited number of studies have examined the effect of CC (beta) chemokines on cytokine production. Taub et al. (14, 24) worked with human T cell clones, demonstrating that several augment IL-2 production in response to anti-CD3-mediated stimulation; the effect on either IFN- or IL-4 production was not evaluated. Using micromolar concentrations (in contrast to the nanomolar levels referred to above) of RANTES, Bacon et al. (28) demonstrated the induction of IL-5 and IL-2 (but not IL-4 or IFN-) cytokine synthesis by long-term human T cell clones. Schrum et al. (29), examining Ag-driven human T cell cytokine and chemokine responses, report that the synthesis of CC chemokines MIP-1, MIP-1ß, and RANTES is preferentially associated with a type 1 immune response.
In animal studies examining the effect of exogenous administration of various CC chemokines on naive T cell commitment to Th1 vs. Th2-like patterns, Karpus et al. (30) demonstrated that MIP-1 enhanced anti-CD3-mediated IFN- (and not IL-4 production), whereas MCP-1 enhanced IL-4 but not IFN- production, in a transgenic mouse model. Others provide in vivo evidence that initial T cell commitment to Th1 vs. Th2 biased patterns may be readily modulated by certain chemokines (31, 32). Conversely, evidence from numerous human and ex~perimental animal systems makes it clear that immune responses, once established, are extremely difficult to redirect. Together, these studies are consistent with the view of chemokines playing an important role in 1) influencing the commitment of naive T cells to Th1 vs. Th2-like patterns and 2) the maintenance of established responses either directly, by signaling through chemokine binding receptors that are expressed on lymphocytes, or secondary to their capacity to promote increased expression of cytokines (i.e., IFN-, IL-12) that have a demonstrated capacity to shape immune responses in vivo.
In marked contrast to the up-regulation of antigen-driven IFN- response, IP-10 down-regulated antigen-driven proliferation of PBMC. It was previously reported that IP-10 inhibits proliferation of human endothelial cells (9) and bone marrow-derived hematopoietic progenitors (12). However, its action on PBMC or on antigen-driven systems has not been examined. The negative costimulator effect of IP-10 on the proliferation of PBMC distinguishes it from two other CXC chemokines, PF4 and IL-8, which were shown to exert no major effect on antigen or anti-CD3 Ab-induced proliferation of human T cells (14, 24). On the other hand, some CC chemokines (RANTES, MIP-1, MIP-1ß, and MCP-1) have been reported to enhance human T cell proliferation (14, 24). The ability of IP-10 to simultaneously enhance antigen-driven IFN- synthesis by PBMC while inhibiting their proliferation suggests that it up-regulates IFN- synthesis by a mechanism independent of the generation of new IFN- secreting cells. At the same time, it is not possible to conclude that the cells producing IFN- are not proliferating or that the expansion of a subset of cells is not responsible for the increase in levels of IFN-.
The mechanism by which IP-10 selectively augments IFN- synthesis remains to be determined. IP-10 was originally discovered as an abundant mRNA species induced by treatment of human monocytic cell lines stimulated with rIFN- (4). Thereafter, several reports of in vivo expression of IP-10 protein in human skin during delayed-type hypersensitivity responses to PPD, after injection of rIFN-, or in the lesions of tuberculoid leprosy, cutaneous leishmaniasis (33), psoriatic plaques (34), contact hypersensitivity (35), and cutaneous T cell lymphoma (CTCL) (36) were reported. The ability of rIL-12 to promote tumor regression in mice was proposed to be mediated by IFN- and was associated with IP-10 induction (37–39). Note, however, that all studies to date have identified and visualized IP-10 as a downstream molecule induced by IFN- directly or subsequent to IL-12 activity. Thus, Sarris et al. (36) proposed that the interaction between IFN- produced by lymphoma cells and IP-10 by keratinocytes was responsible for epidermotropism of CTCL cells. Based on the present study, where IP-10 clearly promotes strong IFN- gene expression by antigen or polyclonally stimulated cells, we propose the existence of a positive amplification loop between IP-10 and IFN- in vivo. Such feedback amplification would help explain the mechanisms of chronic inflammatory conditions such as granulomas, the tissue tropism of tumors such as CTCL, and is consistent with emerging data suggesting that IP-10 plays an important role in the pathogenesis of inflammatory conditions characterized by excessive IFN- production such as delayed-type hypersensitivity responses, granulomas, experimental autoimmune encephalomyelitis, and superantigen-mediated tissue damage (20, 40).
Finally, though in general the CXC, CC, and C families of chemokines preferentially induce chemotactic activity in neutrophils, mononuclear cells, and lymphocytes, respectively, IP-10 differs from most other CXC members in that it targets lymphocytes specifically and has no detectable activity on neutrophils (5, 16). Its activities are most clearly evident on stimulated, but not resting, T cells both for chemotaxis (5) and regulation of cytokine gene expression (this report). This apparently restricted target specificity, paired with the recognized role that T cells play in the pathogenesis and maintenance of allergic disease, suggests that subjects with immediate hypersensitivity to environmental allergens may exhibit altered IP-10 regulation compared to the nonallergic population. Work to address this possibility is currently under way.
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SUMMARY |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUMMARYREFERENCES |
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synthesis and is without effect on IL-4 responses. The findings suggest that IP-10, if expressed at these levels during immune responses, may play an important role in maintaining the bias toward the IFN- dominated (Th1-like), rather than IL-4 dominated, cytokine production exhibited by most individuals to most common antigens. This property of rIP-10 to promote Th1-associated expression is independent of the mode of cellular activation because the same trend was evident when using PHA, anti-CD3, TSST-1, and two collections of common environmental antigens, all of which activate T cells in distinct ways and transduce different signals leading to distinct patterns of cytokine synthesis. These observations raise the possibility that IP-10 may potentially be useful as a therapeutic agent to promote Th1-dominated recall responses in disease conditions that include immediate hypersensitivity disorders and several viral and protozoan infections (20, 40).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Abbreviations: Ag, antigen (or antigens); NK, natural killer; PBMC, peripheral blood mononuclear cells; PHA, phytohemagglutinin; TSST, toxic shock syndrome toxin; CTCL, cutaneous T cell lymphoma; rIFN, recombinant interferon; IP, inducible protein; rhIP-10, recombinant human IP-10; TNF, tumor necrosis factor.
Received for publication October 9, 1997. Accepted for publication January 20, 1998.
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K. Muller, S. Bischof, F. Sommer, M. Lohoff, W. Solbach, and T. Laskay Differential Production of Macrophage Inflammatory Protein 1{gamma} (MIP-1{gamma}), Lymphotactin, and MIP-2 by CD4+ Th Subsets Polarized In Vitro and In Vivo Infect. Immun., November 1, 2003; 71(11): 6178 - 6183. [Abstract] [Full Text] [PDF]
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 J. D. Campbell, M. J. Stinson, F. E. R. Simons, and K. T. HayGlass Systemic chemokine and chemokine receptor responses are divergent in allergic versus non-allergic humans Int. Immunol., November 1, 2002; 14(11): 1255 - 1262. [Abstract] [Full Text] [PDF]
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A. J. Marshall, Q. Du, K. E. Draves, Y. Shikishima, K. T. HayGlass, and E. A. Clark FDC-SP, a Novel Secreted Protein Expressed by Follicular Dendritic Cells J. Immunol., September 1, 2002; 169(5): 2381 - 2389. [Abstract] [Full Text] [PDF]
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N. A. Gasper, C. C. Petty, L. W. Schrum, I. Marriott, and K. L. Bost Bacterium-Induced CXCL10 Secretion by Osteoblasts Can Be Mediated in Part through Toll-Like Receptor 4 Infect. Immun., August 1, 2002; 70(8): 4075 - 4082. [Abstract] [Full Text] [PDF]
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J. N. Kline, K. Kitagaki, T. R. Businga, and V. V. Jain Treatment of established asthma in a murine model using CpG oligodeoxynucleotides Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L170 - L179. |
