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(Journal of Leukocyte Biology. 2002;72:192-198.)
© 2002 by Society for Leukocyte Biology

IL-12 and IL-18 induce MAP kinase-dependent adhesion of T cells to extracellular matrix components

Amiram Ariel*, Daniela Novick{dagger}, Menachem Rubinstein{dagger}, Charles A. Dinarello{ddagger}, Ofer Lider* and Rami Hershkoviz§

* Departments of Immunology and
{dagger} Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel;
§ Department of Internal Medicine D, Assaf-HaRofe Hospital, Rishon Lezion, Israel; and
{ddagger} Division of Infectious Diseases, University of Colorado Health Science Center, Denver

Correspondence: Dr. Ofer Lider, Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: ofer.lider{at}weizmann.ac.il


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cytokines and chemokines play an essential role in recruiting leukocytes from the circulation to the peripheral sites of inflammation by modulating cellular interactions with endothelial cell ligands and extracellular matrix (ECM). Herein, we examined regulation of T cell adhesion to ECM ligands by two major proinflammatory cytokines, interleukin (IL)-12 and IL-18. IL-12 and IL-18 induced T cell adhesion to fibronectin (FN) and hyaluronic acid at low (pM) concentrations that were mediated by specific adhesion molecules expressed on the T cell surface, namely, ß1 integrins and CD44, respectively. The induction of adhesion by IL-12 and IL-18 was inhibited by extracellular signal-regulated kinase and p38 mitogen-activated protein kinase inhibitors (PD098059 and SB203580, respectively). In contrast, IL-12- and IL-18-induced interferon-{gamma} (INF-{gamma}) secretion from T cells was inhibited by SB203580, but not by PD098059. It is interesting that low concentrations of IL-12 and IL-18 induced T cell adhesion to FN in a synergistic manner. Thus, in addition to the regulation of late inflammatory functions such as INF-{gamma} production, IL-12 and IL-18, alone or in combination, regulate early inflammatory events such as T cell adhesion to inflamed sites.

Key Words: adhesion molecules • cellular activation • chemokines • cytokines • inflammation • T lymphocytes


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recruitment of leukocytes from the circulation to the peripheral sites of inflammation depends on adhesive interactions of chemoattracted cells with their surrounding milieu, which occurs through specific adhesion molecules such as integrins and CD44 [1 2 3 4 5 ]. This directed migration is the consequence of a complex "decision-making" process of the recruited cell. Various cytokines and chemokines can mediate or block leukocyte migration, depending on the nature of the mediator, mediator concentration, responding cell type, and presence of other regulatory factors [e.g., other cytokines or chemokines and degradation products of extracellular matrix (ECM) and cytokines] in its vicinity [6 7 8 9 10 ].

Interleukin (IL)-12, which is produced mainly by macrophages and dendritic cells, is a pleiotropic cytokine comprised of disulfide-linked p35 and p40 chains [11 ]. In vivo, IL-12 increases inflammatory responses and anti-tumor activity [12 ], probably due to its ability to induce T and natural killer (NK) cell proliferation as well as the expression of interferon-{gamma} (IFN-{gamma}), IL-18R, and IFN regulating factor-1 [13 14 15 ] and to promote the expression of the T helper cell type 1 (Th1) phenotype by CD4+ T [16 ]. Binding IL-12 to its receptor, which is composed of two noncovalently linked chains [17 , 18 ], activates several signal transduction molecule members of the Janus kinase family [12 , 17 , 19 ].

IL-18 provides an early signal for development of Th1 lymphocyte responses [20 ]. This IL, together with antigens IL-1ß, IL-2, and IL-12 and mitogens, induces the production of IFN-{gamma} [14 , 21 , 22 ]. IL-18 also enhances the production of granulocyte macrophage-colony stimulating factor and IL-12, potentiates anti-CD3-induced T cell proliferation, and increases Fas-mediated killing of NK cells [23 , 24 ]. Some IL-18-mediated activities require up-regulation of IL-18 receptor expression [14 , 25 , 26 ]. The IL-18 receptor is comprised of at least two transmembane chains, an IL-18 receptor {alpha} chain (IL-18R; previously known as IL-1 receptor-related protein) and an accessory protein-like chain, which belongs to the IL-1R family [27 , 28 ]. IL-18 shares with IL-1 and tumor necrosis factor family members several signaling mechanisms, such as the activation of the IL-1R-activating kinase, nuclear factor (NF)-{kappa}B-inducing kinase, and others [29 30 31 ], which result in the translocation of NF-{kappa}B to the nucleus and transcription of this kinase’s target genes [32 ].

Herein, the effect of IL-12 and IL-18 on the interactions of T cells with ECM2 ligands was examined. IL-12 and IL-18 induced a p38 mitogen-activated protein kinase (MAPK)- and extracellular-regulated kinase (ERK)-dependent T cell adhesion to the ECM components fibronectin (FN) and hyaluronic acid (HA). The proadhesive action of these cytokines was increased in a synergistic manner when cytokines were applied together.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The following reagents were obtained as indicated: IL-12 (Cytolab, Rehovot, Israel); IL-18 (Serono, Geneva, Switzerland); bovine serum albumin (BSA) and HA (Sigma Chemical Co., St. Louis, MO); FN (Chemicon, Temecula, CA); and HEPES buffer, antibiotics, cosmic calf serum (CCS), and RPMI 1640 (Beit-Haemek, Kibutz Beit-Haemek, Israel). The following monoclonal antibodies (mAb) were also used: purified and biotinylated mouse anti-human IFN (PharMingen, San Diego, CA); and anti-{alpha}2, {alpha}4, {alpha}5, and ß1 integrins and anti-CD44 (Serotec, Oxford, UK). PD098059, SB203580, and mAb against total ERK and p38 MAPK were generously provided by Dr. Roni Seger (Weizmann Institute of Science).

Purification of human T cells
T cells from human peripheral blood were isolated on a Ficoll gradient, washed, resuspended in phosphate-buffered saline containing 3% heat-inactivated fetal calf serum, and incubated (45 min, 37°C in a 7% CO2-humidified atmosphere) on nylon-wool (Fenwall, IL) columns. The nonadherent cells were eluted and washed, and the remaining platelets were removed by centrifuging the cells (700 rpm, 15 min, 18°C). To remove the remaining monocytes, we incubated the cells (2 h) on tissue culture grade Petri dishes. Thus, the cells obtained contained >92% CD3+ cells.

T cell adhesion assays
The adhesion of the purified human T cells to immobilized substrates of the ECM was examined as previously described [10 , 33 ]. Briefly, 51[Cr]-labeled T cells [105 cells in 100 µl RPMI containing 0.1% BSA (adhesion medium)] were added to flat-bottomed microtiter wells that had been precoated with FN (0.5 µg/well) or HA (5 µg/well) and blocked with 1% BSA. Various concentrations of IL-12 and/or IL-18 were added to the cells, and the plates were incubated (60 or 180 min at 37°C in a humidified, 7.5% CO2 atmosphere) and then washed. Anti-{alpha}2, {alpha}4, {alpha}5, or ß1 integrins or CD44 mAb, PD098059, or SB203580 were added to some wells along with the cells. The adherent cells were lysed with detergent in adhesion medium, and the resulting supernatants were analyzed with a {gamma}-counter. Results were expressed as the mean percentage ± SD of bound T cells from quadruplicate wells.

IFN-{gamma} secretion assay
Freshly isolated T cells were cultured for 24 h in RPMI 1640 containing 5% heat-inactivated CCS, 1% HEPES, and antibiotics (culture media) at 37°C in a humidified, 7.5% CO2 atmosphere and were then transferred to activation media that contained 1% BSA instead of CCS. The cells were activated by IL-12, IL-18, or IL-12 and IL-18 for 18 h at 37°C in a humidified, 7.5% CO2 atmosphere, after which the supernatants were collected, and their IFN-{gamma} levels were determined using a PharMingen mAb. Where indicated, PD098059 or SB203580 was added to the cell cultures prior to the addition of the cytokines.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
IL-12- and IL-18-mediated induction of T cell adhesion to FN and HA
Several cytokines induce adhesion of T cells to intact endothelial cells, basement membranes, and ECM and to their components [1 , 4 , 7 , 10 ]. Therefore, we examined whether IL-12 and IL-18 affect adhesion of human resting T cells to FN and HA. IL-12 and IL-18 induced T cell adhesion to FN and HA in a dose-dependent manner (Fig. 1A and 1B ). No adhesion was induced when BSA was used as an adhesive substrate (Fig. 1C) . It is interesting that even low concentrations (0.5–5 pg/well) of either of these cytokines significantly increased adhesion of the T cells to FN or HA. Maximal adhesion induced by IL-12 occurred at cytokine concentrations (0.5–5 pg/well) lower than those (5–50 pg/well) required for maximal/eqivalent IL-18-induced adhesion. The kinetics of IL-12- and IL-18-mediated adhesion to FN and HA was similar, although the time of initiation (data not shown) differs. Thus, IL-12 and IL-18 are potent stimulators of T cell adhesion to various ECM substrates.



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  		Figure 1. Induction of T cell adhesion to FN and HA by IL-12 and IL-18. [51Cr]-Labeled human T cells were activated with IL-12 or IL-18, seeded onto FN (A)-, HA (B)-, or BSA (C)-coated wells, and incubated for 60 (A and C) or 180 min (B) at 37°C. Afterwards, nonadherent T cells were removed, the adherent cells were lysed, and the percentage of T cells that had adhered was determined. One experiment is representative of four.

 
IL-12- and IL-18-induced adhesion of T cells to FN and HA is mediated by ß1 integrins and CD44, respectively
Different receptors on the surface of T cells mediate their interactions of various ECM moieties [2 ]. Therefore, we examined which adhesion molecules are involved in T cell interactions with FN and HA induced by IL-12 and IL-18. IL-12- and IL-18-stimulated adhesion to FN was inhibited by antibodies directed against {alpha}4, {alpha}5, or ß1 integrins, but not by anti-{alpha}2 integrin or -CD44 mAb. Conversely, the adhesion to HA induced by IL-12 and IL-18 was inhibited by anti-CD44 but not by any anti-integrin antibodies (Fig. 2A and 2B ). Thus, the adhesion of T cells to FN, induced by IL-12 and IL-18, is mediated by {alpha}4, {alpha}5, and ß1 integrins, and the adhesion to HA is mediated by CD44.



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  		Figure 2. Inhibition of IL-12- and IL-18-induced adhesion of T cells to FN and HA by antibodies directed against adhesion receptors. Labeled human T cells were seeded onto FN (A)- or HA (B)-coated wells together with IL-12 (1 ng/ml) or IL-18 (10 ng/ml) and mAb against {alpha}2, {alpha}4, {alpha}5, or ß1 integrins or CD44 (1 µg/ml). After 60 or 180 min at 37°C, T cell adhesion was determined. One experiment is representative of three.

 
MAPK is involved in the IL-12- and IL-18-induced T cell adhesion to FN and IFN-{gamma} secretion
As IL-12 and IL-18 induce the activation of MAPK in various cell types [34 , 35 ], involvement of ERK and p38 MAPK in IL-12- and IL-18-mediated induction of T cell adhesion to FN was examined. T cells were activated with IL-12 or IL-18 in the presence of the ERK inhibitor PD098059 or the p38 MAPK inhibitor SB203580, and their adhesion to FN was measured. Both of these inhibitors inhibited the IL-12- and IL-18-stimulated adhesion of T cells to FN and with similar kinetics (Fig. 3A and 3B ). The adhesion induced by IL-12 or IL-18 was not inhibited by treatment with dimethyl sulfoxide (0.05%), which was used to dissolve the inhibitors. Note that higher concentrations of PD098059 and SB203580 were required to inhibit the IL-12-induced rather than the IL-18-induced T cell adhesion, which suggests that IL-12 induces a stronger signal than IL-18.



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  		Figure 3. Inhibition of IL-12- and IL-18-induced adhesion of T cells to FN by MAPK inhibitors. Labeled human T cells were seeded onto FN-coated wells together with IL-12 (1 ng/ml) or IL-18 (10 ng/ml) and PD098059 (A) or SB203580 (B). After 60 min at 37°C, T cell adhesion was determined. One experiment is representative of three.

 
The role of MAPK in the regulation of IL-12- and IL-18-mediated events in T cells was examined further by monitoring the secretion of IFN-{gamma} 18 h after stimulating T cells with IL-12 alone or together with IL-18 in the presence of ERK or p38MAPK inhibitors. IL-12 induced a minor secretion of IFN-{gamma}, which was inhibited by SB203580, but not by PD098059 (Fig. 4A ). When T cells were activated by IL-12 and IL-18, a synergy in IFN-{gamma} secretion occurred, which was also inhibited by SB203580, but not by PD098059 (Fig. 4B) . It is interesting that the concentrations of SB203580 that inhibited IFN-{gamma} secretion were higher than those required to inhibit cell adhesion, indicating that cell adhesion is more sensitive tomodification of its generating signal. The dose of SB203580 required to inhibit IL-12- plus IL-18-mediated IFN-{gamma} secretion was higher than the dose required to inhibit the secretion of IFN-{gamma} mediated by IL-12 alone, which indicates a synergy between IL-12 and IL-18. Thus, while IL-12- and IL-18-induced T cell adhesion to FN requires activation of ERK and p38 MAPK, only activation of p38 MAPK is necessary for the induction of IFN-{gamma} secretion by these cytokines.



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  		Figure 4. Inhibition of IL-12- and IL-18-induced secretion of IFN-{gamma} from T cells by MAPK inhibitors. Isolated human T cells were incubated with IL-12 (25 ng/ml; A) or IL-12 and IL-18 (50 ng/ml; B) in the presence of PD098059 (PD) or SB203580 (SB). After 18 h of incubation at 37°C, the supernatants were collected, and their levels of IFN-{gamma} were determined using a standard enzyme-linked immunosorbent assay. One experiment is representative of four.

 
Analysis of synergy of IL-12- and IL-18-induced T cell adhesion to FN
As IL-12 and IL-18 induce synergistic effects on several inflammatory functions of immune cells [13 , 30 ], we examined the synergistic effects of these cytokines that also apply to T cell adhesion to FN. Low concentrations of IL-12 and IL-18, which alone did not induce an apparent strong adhesive response, were found to be markedly proadhesive when combined (Fig. 5 ).



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  		Figure 5. Induction of T cell adhesion to FN by combinations of IL-12 and IL-18. Labeled human T cells were activated by IL-12, IL-18, or both and were seeded onto FN-coated wells and incubated for 60 min at 37°C. After which, T cell adhesion was determined. One experiment is representative of four.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
During the progression of the inflammatory reactions, various proinflammatory mediators are formed. These mediators assist immunocytes in performing proactive functions, such as interacting with surrounding ECM and migration toward an injured or inflamed site [3 , 36 , 37 ]. To orchestrate such complex processes efficiently and accurately and maintain homeostasis, signals of mediators in the vicinity of migrating cells are merged. The outcome is a tight regulation and "decision-making" process that enforces not only the inflammatory condition, but also its rapid termination or continuation if necessary [6 , 10 , 38 39 40 ]. Herein, we showed that two major proinflammatory cytokines, IL-12 and IL-18, are potent inducers of T cell adhesion to the ECM ligands FN and HA. We postulate that these adhesive interactions are a prerequisite for directional movement of T cells to inflamed sites. We also found that exposure of T cells to a combination of IL-12 and IL-18 can evoke a beneficial response over the stimulation with each cytokine alone. This effect is valid for several proinflammatory functions, such as IFN-{gamma} secretion and cell adhesion to ECM components when T cells are exposed to these cytokine alone.

Adhesive interactions of T cells with ECM components, such as FN and HA, are mediated by adhesion molecules such as ß1 integrins and CD44, respectively, which modulate their binding properties upon activation of the cells [2 , 41 , 42 ]. We showed that IL-12 and IL-18 induce firm adhesive interactions specifically between T cells and ECM components through very late antigen (VLA)-4, VLA- 5, and CD44 molecules on the cells. Regulation of cell adhesion, cell migration, and the activity of several cytokines and chemokines is mediated by MAPKs [43 44 45 46 ]. Therefore, involvement of ERK and p38 MAPK in IL-12- and IL-18-induced adhesion of T cells to FN was examined with the specific ERK and p38 MAPK inhibitors, PD098059 and SB203580, respectively. IL-12 and IL-18 induced T cell adhesion to FN in an ERK- and p38-dependent manner. The concentrations of PD098059 and SB203580 that inhibited cell adhesion are much lower than the EC50 values for both compounds, which are 5 and 0.6 µM, respectively. However, these concentrations of PD098059 and SB203580 also inhibit T cell adhesion induced by other cytokines and chemokines, such as IL-2 and macrophage-inflammatory protein-1ß (data not shown). Therefore, it is possible that ERK and p38 MAPK are involved in integrin-generated signaling, which leads to cytoskeletal rearrangement and cell spreading, regardless of the stimulation used. The signal induced by IL-12 appears to be stronger than that induced by IL-18, as lower amounts of ERK and p38 MAPK inhibited IL-18-induced adhesion as compared with the IL-12-induced adhesion. Furthermore, less IL-12 (5 pg/well) than IL-18 (50 pg/well) was needed to induce maximal T cell adhesion. At physiological concentrations, IL-12 and IL-18 induce significant adhesion of T cells to ECM moieties [47 ]. It is interesting that the secretion of IFN-{gamma}, a major characteristic of IL-12- and IL-18-stimulated T cells, was dependent on the activity of p38 MAPK but not on ERK activity, as was previously shown for IL-12-stimulated T cells [38 ].

IL-12 and IL-18 can cooperate in the generation of inflammatory and autoimmune disorders in vivo [48 , 49 ], as well as in the activation of immune cells [22 , 50 ]. Activation by IL-12 of T cells induces elevated expression of their IL-18 receptors, a prerequisite for induction by IL-18 of IFN-{gamma} secretion from T cells [25 , 26 ]. Herein, IL-12 and IL-18, at concentrations that induced submaximal adhesion separately, induced adhesion of T cells synergistically to FN. However, with high concentrations at which IL-12 and IL-18 alone promote maximal cell adhesion, a combination of the two had no beneficial effect. These results suggest that IL-12 and IL-18 can "cross talk" in their early and late signaling events. Interestingly, it has been recently shown that IL-12 can induce the expression of CCR5 on CD4+ Th1 cells and thereby affect their lymphocyte function-associated antigen-1-mediated cellular adhesiveness. This IL-12-dependent event was up-regulated in the presence of IL-18, which increased the expression of RANTES but not CCR5 [51 ].

In this work, we examined the response of T cells to their dynamically changing environment, which, in time, encounters an increasing number of signals. We also investigated how these signals are integrated by T cells in order to culminate in adhesive interactions with their milieu. Our findings indicate that certain proinflammatory mediators, such as IL-12 and IL-18, can use specific adhesion receptors and specific signaling elements to strengthen their interactions with tissue components and possibly thereby regulate their migration to inflamed sites. This regulation by different cytokines can be done in a collaborative manner and thereby strengthen the short-term activatory functions of one another.


   ACKNOWLEDGEMENTS
 
This study was supported by research grants from The Israel Academy of Sciences and Humanities and The Robert Koch-Minerva Center for Research in Autoimmune Diseases (The Weizmann Institute and Munich, Germany, respectively) and the Center for Emerging Diseases (Israel; to O. L.) and the Ares Serono Group of Companies (to M. R.). A. A. was funded by The Samara Jan Turkel Scholarship Fund for Autoimmune Diseases. M. R. is the Edna and Maurice Weiss chair of cytokine research. O. L. is the incumbent of the Weizmann League Career Development Chair in Children’s Diseases. We thank Dr. Barbara Schick for reviewing the manuscript.

Received November 23, 2001; revised January 31, 2002; accepted February 6, 2002.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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