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The Journal of Immunology, 2003, 171: 4990-4994.
Copyright © 2003 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Vasoactive Intestinal Peptide Acts as a Potent Suppressor of Inflammation In Vivo by Trans-Deactivating Chemokine Receptors 1

Michael C. Grimm2,*,{dagger}, Rosie Newman*,{dagger}, Zeenath Hassim*,{dagger}, Natalia Cuan*,{dagger}, Susan J. Connor*,{dagger}, Yingying Le{ddagger}, Ji Ming Wang{ddagger}, Joost J. Oppenheim{ddagger} and Andrew R. Lloyd{dagger}

* Department of Medicine, St. George Clinical School and {dagger} Inflammation Research Unit, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia; and {ddagger} Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, MD 21702


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Chemokines mediate trafficking of leukocytes to sites of inflammation and immune responses through activation of G protein-coupled receptors, which thereby provide appealing targets for novel anti-inflammatory agents. Vasoactive intestinal peptide (VIP) is an immunosuppressive neurotransmitter. We show that VIP inhibited the function of chemokine receptors on monocytes and CD4+ T lymphocytes, with impaired chemotaxis and calcium flux in response to the cognate chemokine ligands CXCL12, CCL3, CCL4, and CCL5. This was mediated by VIP receptor type 1 and was not caused by chemokine receptor internalization. However, VIP caused dose-dependent phosphorylation of the chemokine receptor CCR5. This trans-deactivation process was studied in a murine model of delayed-type hypersensitivity: continuous infusion of VIP resulted in significant abrogation of monocyte and lymphocyte infiltration. Circulating mononuclear cells from VIP-infused mice were unable to respond to chemokines. VIP may provide a novel approach to treatment of inflammatory diseases through inhibition of chemokine-dependent leukocyte recruitment.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Leukocyte trafficking is fundamental for immune responses and inflammation, as well as for the development of secondary immune tissues. Chemokines are key mediators of leukocyte chemotaxis to inflammatory sites in ailments including infectious diseases (1), asthma (2), rheumatoid arthritis (3), and inflammatory bowel disease (4, 5), and diseases hitherto thought noninflammatory, such as atherosclerosis (6).The key role of chemokines and their receptors in disease is highlighted by their subversion by pathogens such as herpesviruses, poxviruses, and HIV (7). Factors that mitigate chemokine functions are therefore desirable as therapeutic agents. Gene deletion animals and inhibition studies of specific chemokine receptors, however, suggest significant overlap in function. Thus, novel therapeutic strategies are required to target a number of receptors simultaneously to abrogate leukocyte recruitment and activation pathways.

Vasoactive intestinal peptide (VIP) 3 is an immunomodulatory neuropeptide. It attracts monocytes and T cells (8), alters costimulatory activity of APCs (9), abrogates innate immunity (10), and polarizes Th2 T cells (11). VIP is constitutively expressed in some lymphoid microenvironments (12, 13, 14) and may play a modulating role for lymphocyte activity in those sites. Our previous demonstration that opioids trans-deactivate chemokine receptors through their phosphorylation (15) led us to question the ability of VIP to regulate chemokine receptor function. We show that monocyte and CD4+ T cell responses to chemokines are inhibited by exposure to VIP through the VIP receptor type 1 (VPAC-1) receptor and that this is caused by chemokine receptor phosphorylation. VIP infusion in murine delayed-type hypersensitivity (DTH) results in deficient recruitment of monocytes and lymphocytes. These data indicate that VIP trans-deactivates chemokine receptors and this anti-inflammatory function may serve as a model for novel therapies.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Cells

Human monocytes and T cells were isolated from healthy donors: monocytes by using CD14 microbeads (MACS; Miltenyi Biotec, Auburn, CA) and CD4+ and CD8+ T cells by negative selection using microbeads. Purity of enriched cells was >90% by flow cytometry.

Chemotaxis assays

Chemotaxis was performed as described previously (15). Cells were incubated at 37°C with medium, VIP (Sigma-Aldrich, St. Louis MO), the VPAC-1 agonist [Ala11, 22, 28]VIP (Bachem, Switzerland), the VIP receptor antagonist [D-p-cl-Phe6, Leu17]-VIP (Sigma-Aldrich), or the VPAC-1 antagonist ([Acetyl-His1,D-Phe2,Lys15,Arg16]VIP(3-7)GRF(8-27)-NH2) (Phoenix, Belmont CA) for 10 min before VIP or antagonist alone. Cells were washed twice in medium. Chemotaxis was assessed in 48-well chambers using polyvinylpyrrolidone-free 5-µm pore size membranes (Nucleopore; NeuroProbe, Cabin John, MD). The results from >=3 separate experiments are expressed as a percentage of control (medium incubated) chemotaxis.

Calcium mobilization assays

Monocytes were incubated at 107/ml for 30 min at room temperature in HBSS containing 0.1% BSA and 1 µM fura-2 (16), washed in PBS, and incubated with VIP, with or without antagonist. fura-2 excitation was assessed at 340 and 380 nm with detection at 510 nm in a spectrometer using FL WinLab software (PerkinElmer/Cetus, Norwalk, CT), following stimulation with chemokine.

Chemokine receptor flow cytometry

Blood leukocytes were exposed to medium or 10-9M VIP for 60 min, fixed in 1% paraformaldehyde, and then labeled using anti-chemokine receptor Abs (R&D Systems, Minneapolis, MN). Analysis was conducted on a FACScan flow cytometer (BD Biosciences, Mountain View, CA).

Serine phosphorylation of CCR5

Monocytes were incubated with VIP or CCL4 for 60 min at 37°C and lysed in 1% Triton X-100 with 1 mM PMSF, 5 µg/ml aprotinin, 5 µg/ml leupeptin, 1 mM vanadate, and 1 mM EGTA. One microgram of anti-phosphoserine Ab (Zymed Laboratories, San Francisco, CA) was added to 200 µg cell lysates and incubated at 4°C overnight. The complex was captured using protein A-Sepharose at 4°C for 2 h, pelleted, resuspended, and boiled for 5 min to elute the immune complex. After electrophoresis on 4–12% SDS-PAGE precast gels (NOVEX, San Diego, CA), the proteins were transferred to Immobilon P membranes (Millipore, Bedford, MA). Membranes were incubated with 1 µg/ml of a polyclonal Ab specific for CCR5 and not other CC chemokine receptors (Millenium Biotechnology, Ramona, CA) (17), then HRP-conjugated goat anti-rabbit IgG (1/5000; Sigma-Aldrich), followed by Super Signal Chemiluminescent Substrate (Pierce, Rockford, IL).

DTH response to dinitrofluorobenzene (DNFB)

Eight-week-old male BALB/c mice were sensitized by painting of the shaved abdominal wall with DNFB (Sigma-Aldrich) as described previously (18). Repainting was performed at 24 h. At 8 days, animals were anesthetized and Alzet miniosmotic pumps (Alzet, Palo Alto, CA) loaded with 5 x 10-5 M VIP or saline were inserted s.c.. DNFB was painted on the earlobe to generate a DTH response. At 48 h, earlobe thickness was measured and the animals were sacrificed. Serum was collected to determine VIP levels; blood mononuclear cells were obtained for chemotaxis assays. Earlobes were removed and fixed in Formalin and tissue sections were stained with H&E. Mononuclear cells and neutrophils were enumerated by a microscopist blinded to treatment allocation.


   Results and Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Following 30–60 min of VIP exposure, at an optimal concentration of 10-9 M, there was impaired monocyte chemotaxis in response to chemokines including CCL3 (macrophage-inflammatory protein 1{alpha}), CCL4 (macrophage-inflammatory protein 1{beta}), CCL5 (RANTES), and CXCL12 (Fig. 1A). This occurred across the range of chemotactic concentrations of chemokine and suggests dominant inhibition of the cognate receptors CXCR4 and CCR5. Inhibition was prevented by pretreatment of the cells using the VIP receptor antagonist, [D-p-cl-Phe6, Leu17)]-VIP, indicating the effect was mediated through a specific VIP receptor. The inhibitory activity of VIP was transient, with restitution of normal chemotactic responses following 4–5 h of incubation in VIP-free medium (data not shown). Resting CD4+, but not CD8+, T cells also respond to VIP (8) and express VIP receptors (19). Human CD4+ and CD8+ T cells had chemotactic responsiveness to CXCL12 determined following exposure to VIP. CD4+ T cell chemotaxis to CXCL12 was significantly impaired after VIP exposure in a dose-dependent fashion (Fig. 1B), while chemotaxis of CD8+ T cells was not affected. Similar to the effect in monocytes, VIP inhibited CXCL12-induced chemotaxis of T cells across the full chemotactic range. The VIP effect on PBMCs was replicated using the VPAC-1 receptor agonist, [Ala11, 22, 28]VIP, while the specific VPAC-1 receptor antagonist prevented the VIP effect (Fig. 1C), showing that this effect is mediated through the VPAC-1 receptor.



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  		FIGURE 1. Differential functional impairment of chemokine responses by VIP. A, Human monocyte chemotaxis to various chemoattractants following exposure of cells to 10-9 M VIP for 60 min. Results expressed as percent ± SE of untreated monocyte chemotaxis, at peak chemoattractant concentration, from >=3 experiments. *, p < 0.05; **, p < 0.01 by Student’s t test. B, Human CD4+ T cell migration in response to CXCL12 after preincubation with VIP at a range of concentrations. Significant inhibition (p = 0.0002) of CD4+ T cell chemotaxis was seen (repeated measures ANOVA). C, Human PBMC migration to CXCL12 without or with preincubation with 10-9 M VIP, 10-9 M VPAC-1 receptor agonist ([Ala11,22,28]VIP), or 10-5 M VPAC-1 receptor antagonist ([Acetyl-His1,D-Phe2,Lys15,Arg16]VIP(3–7)GRF(8–27)-NH2) for 10 min followed by 10-9 M VIP. Results expressed as percent ± SE of untreated PBMC chemotaxis at peak CXCL12 concentration. *, p < 0.05 vs control; **, p < 0.001 vs control; {dagger}p < 0.01 vs VIP treated by Student’s t test. D, Ca2+ flux in human monocytes stimulated by CXCL12 following treatment with VIP. E, Ca2+ flux in human monocytes stimulated by fMLP, CCL3, and CCL2 following treatment with VIP.

 
We showed that opioids impair chemotaxis, but their effect on intracellular Ca2+ flux induced by chemokines was negligible (15). We therefore analyzed monocyte Ca2+ flux following VIP exposure. VIP caused a dose-dependent inhibition of monocyte Ca2+ flux in response to CXCL12 (Fig. 1D). Monocyte Ca2+ flux responses to fMLP, CCL2 (monocyte chemotactic protein 1) and CCL3 were not impaired (Fig. 1E). VIP failed to induce Ca2+ flux responses and did not induce immediate desensitization of the Ca2+ flux response to chemokines (data not shown), indicating a time-dependent phenomenon. These data demonstrate that analogous to inhibition of chemokines by opioids, VIP induces a differential functional impairment of specific chemokine receptors, with abrogation of multiple CXCR4 signaling pathways, but impairment of chemotaxis only, when mediated by other receptors.

Several mechanisms were considered for these observations. Homologous desensitization of chemokine receptors by cognate ligands results in rapid, but reversible, receptor internalization from the cell surface (20). Conversely, trans-deactivation of chemokine receptors by opioids, while causing impairment of receptor function, had no effect on cell surface receptor expression, excluding receptor internalization as a mechanism (15). Flow cytometry was used to analyze expression of CXCR4 and CCR5 on human blood mononuclear cells. Although CXCR4 decreased in response to its ligand, CXCL12, VIP produced no change in CXCR4 expression (Fig. 2A). Similarly, CCR5 expression was not altered following exposure to VIP (Fig. 2B), although both CCL3 and CCL4 induced significant internalization.



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  		FIGURE 2. Flow cytometry of chemokine receptor expression in response to VIP. A, Flow cytometry showing CXCR4 expression on human PBL after 30-min exposure to CXCL12, 1 µg/ml and 5 µg/ml, or after 60-min exposure to VIP, 10-9 M. B. Flow cytometry showing CCR5 expression on human PBL after 30-min exposure to CCL3 and CCL4, 5 µg/ml, or after 60-min exposure to VIP, 10-9 M.

 
Phosphorylation of intracellular domains of chemokine receptors has been shown to cause uncoupling from G proteins (21). For homologous desensitization, this process is mediated by G protein-coupled receptor kinases (22). Inhibition of receptor function caused by binding of ligands to different receptors (heterologous desensitization) usually results from activation of kinases such as protein kinase C (PKC) (23). We explored the phosphorylation of CCR5 in monocytes following VIP exposure. Monocytes incubated with CCL4 demonstrated phosphorylation of serine residues in CCR5 (Fig. 3A); as predicted. VIP induced a dose-dependent serine phosphorylation of CCR5 from monocytes, with the peak effect in the nanomolar range (Fig. 3A), as was observed for functional inhibition of chemokine activities on monocytes. Phosphorylation of CCR5 induced by VIP was reduced to background levels by staurosporine (Fig. 3B), supporting the involvement of PKC or related kinases in this process. Taken together, these experiments demonstrated that VIP-mediated inhibition of chemokine function was not caused by receptor internalization, but rather by PKC-induced phosphorylation of chemokine receptors.



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  		FIGURE 3. CCR5 phosphorylation in response to VIP. A, Monocytes were treated with VIP for 60 min at 37°C or with CCL4 for 5 min. Serine phosphorylated CCR5 was immunoprecipitated using anti-phosphoserine Ab. Inset, immunoblotting of 40 µg whole monocyte lysate with anti-CCR5 Ab. B, The effect of staurosporine (Stauro; 2.5 ng/ml, 30 min) on CCR5 phosphorylation induced by CCL4 (100 nM, 5 min) or VIP (1 nM, 60 min).

 
To illustrate the in vivo significance of these observations, we used a murine model of DTH (18). Eight-week-old BALB/c mice were sensitized by painting DNFB on the shaved abdominal wall. On day 8, one ear was painted with DNFB to elicit a DTH response. This resulted in pronounced inflammation of the pinna, with edema and infiltration by neutrophils, monocytes, and lymphocytes. Sensitized mice were infused with saline or VIP (5 x 10-5 M, 100 µl) over 3 days. VIP infusion resulted in serum levels of 5.11 ± 1.54 x 10-9 M (n = 5), as determined by RIA, while saline-infused mice had undetectable serum VIP. The earlobe inflammation in saline-infused mice was indistinguishable from that seen in noninfused mice (Fig. 4A). However, in mice infused with VIP, there was a pronounced reduction in cellular infiltration of the dermal tissues of the ear, with residual neutrophils (Fig. 4A). Histomorphometry demonstrated an 81% reduction in the numbers of mononuclear cells in the DTH-affected earlobes of VIP-treated mice compared with saline-infused mice (p < 0.02; Fig. 4B), while neutrophil numbers were not altered. These observations are consistent with previous data showing that neutrophils do not express VIP receptors (24, 25). VIP infusion resulted in virtually complete abrogation of blood mononuclear cell migration in response to CCL2 (Fig. 4C) as well as to several other chemokines, including CXCL10, CXCL12, CCL3, CCL4, and CCL19. Although the completeness of inhibition contrasts with the partial abrogation of human chemotaxis shown in Fig. 1, these differences may be species and time dependent. In sum, these data show that the abrogation of chemokine-mediated monocyte and CD4+ T lymphocyte migration observed in vitro after VIP treatment correlated with an in vivo ability of VIP to impair mononuclear cell recruitment in a model of DTH.



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  		FIGURE 4. Effect of VIP infusion on development of DTH responses in the earlobe induced by DNFB. A, Histology of earlobes showing acetone painting in DNFB-sensitized mice, the effect of saline infusion on DTH induced by DNFB painting in sensitized mice, and the effect of VIP infusion on DTH induced by DNFB painting in sensitized mice. B, Mononuclear cell counts, per 100-µm cartilage, in DTH response following saline or VIP (n = 5 mice/group; two separate experiments). Statistically significant differences as determined by Mann-Whitney U test. C, Chemotaxis of PBMC from mice infused with VIP in response to CCL2 (n = 3 mice/group). *, p < 0.05; **, p < 0.01 by Student’s t test.

 
Chemokines and their receptors are critical to the recruitment of inflammatory cells to sites of Ag exposure and phlogistic stimuli. Inhibition of these mediators has so far relied on perturbing individual chemokines or receptors, but extrapolating these studies to clinical contexts is problematic because of the functional redundancy in the chemokine system. We demonstrate here that a number of chemokine receptors can be simultaneously and reversibly impaired by a process of trans-deactivation by VIP. The process is selective for monocytes and CD4+ T cells, is mediated through the VPAC-1 receptor, and is effected by PKC-induced chemokine receptor phosphorylation. The inhibitory activity of VIP can be utilized in vivo to abrogate a DTH response. These studies support and extend the anti-inflammatory effects of VIP observed by Delgado et al. (26) in a rat model of collagen-induced arthritis. Indeed, disease prevention in that model was accompanied by markedly reduced mononuclear cell infiltration as well as reduced chemokine production (26), and this latter point might partly explain our own in vivo observations.

VIP may also play a role in the physiological control of chemokine functions. Although a role for VIP in controlling physiological lymphocyte recirculation must be clarified before clinical interventions with VIP can be considered, our studies highlight the potential for trans-deactivating agents such as VIP to be used for inflammatory diseases.


   Acknowledgments
 
We thank Drs. N. Tedla and T. Hampartzoumian for assistance with the DTH, Dr. A. Sharpe for VIP RIAs, and Drs. Z. Howard and M. Davenport for critical advice.


   Footnotes
 
1 This work was supported by National Health and Medical Research Council Australia 113853, the Sylvia and Charles Viertel Foundation, and the Gastroenterological Society of Australia. Back

2 Address correspondence and reprint requests to Dr. Michael C. Grimm, Department of Medicine, St. George Clinical School, Kogarah, NSW 2217, Australia. E-mail address: M.Grimm{at}unsw.edu.au Back

3 Abbreviations used in this paper: VIP, vasoactive intestinal peptide; VPAC-1, VIP receptor type 1; DNFB, dinitrofluorobenzene; DTH, delayed-type hypersensitivity; PKC, protein kinase C. Back

Received for publication November 25, 2002. Accepted for publication September 24, 2003.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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