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VASCULAR BIOLOGY
B transactivation and chemokine response in murine macrophages via ERK1/2 and p38 MAPK signaling pathwaysDepartment of Pharmacology, National University of Singapore, Singapore
Submitted 29 February 2008 ; accepted in final form 22 April 2008
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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B-dependent NF-B activation and enhanced DNA binding as well as transactivation activity of the transcription factor. SP-evoked transcriptional induction of chemokines was specific, since it was blocked by treatment with selective neurokinin-1 receptor antagonists. Moreover, SP stimulation of macrophages activated the ERK1/2 and p38 MAPK but not JNKs. Blockade of these two MAPK pathways with specific inhibitors abolished SP-elicited nuclear translocation of phosphorylated NF-B p65 and NF-B-driven chemokine production, suggesting that the two MAPKs lie in the signaling pathways leading to the chemokine response. Collectively, our data demonstrate that SP enhances selective inflammatory chemokine production by murine macrophages via ERK/p38 MAPK-mediated NF-B activation. neuropeptides; monocytes/macrophages; protein kinases; transcription factors; chemokines
via its COOH terminus (30). It induces nitric oxide production and oxidative burst of macrophages, resulting in the production of reactive oxygen intermediates (42). SP also enhances antigen presentation and phagocytosis by macrophages during cellular immune responses. Although it is evident that SP contributes to macrophage-mediated inflammatory responses, no study has so far investigated the effect of SP on the production of inducible chemokines by macrophages. During inflammation, activated resident macrophages secrete chemokines that attract neutrophils, T cells, and additional macrophages (36) and perpetuate the inflammatory responses. Inflammatory/inducible chemokines play a central role in leukocyte trafficking to areas of tissue injury in response to physiological stress, and their expression is documented in a variety of disorders associated with leukocyte infiltration, including neuroinflammation, allergic inflammatory disease, cardiovascular disease, autoimmune disease, transplantation, cancer, and human immunodeficiency virus-associated disease (13). Our earlier work in vivo has suggested that during acute inflammation, SP induces chemokine release from macrophages infiltrating into local and distant damaged tissues (37). This has prompted us to investigate the direct stimulatory effect of SP on chemokine release from macrophages and the mechanistic pathways involved.
Among the main signaling pathways leading to chemokine responses, the MAPK and transcription factor NF-B pathways are the most prominent ones (6, 43). MAPKs are a family of proline-directed protein serine/threonine kinases activated by a cascade of intracellular phosphorylation events and transduce signals from the cell surface to the nucleus (7, 11, 17). MAPKs consist of four subfamilies, the best characterized of which are the ERK1/2, JNKs, and p38 MAPK. Every MAPK subfamily is composed of a three sequentially acting kinase module, MEKK, MEK, and MAPK, each one activating the next via phosphorylation. Their substrates, located in the cytoplasm as well as in the nucleus, include other kinases, transcription factors, phospholipases, and cytoskeletal proteins (23, 32, 35). In general, ERK1/2 are mainly involved in anabolic processes, such as cell division, growth, and differentiation, whereas JNKs and p38 MAPK are mostly associated with cellular responses to stress conditions (19, 23, 32, 35). NF-B is the central regulator for expression of genes involved in inflammatory and immune responses (15). In the classic pathway, activation of NF-B, especially the most abundant form, p50/p65 heterodimer, depends on the phosphorylation of its endogenous inhibitor IB, mainly by IB kinases (IKKs). This leads to ubiquitination and proteasomal degradation of IB. The liberated NF-B dimer then translocates to the nucleus, where it activates specific target genes (2, 18). Growing evidence indicates posttranslational modifications of NF-B, particularly phosphorylation and acetylation, also play significant roles in the activation of the transcription factor (8, 20). In response to certain stimuli, the transactivation potential of NF-B is regulated by phosphorylation of its p65 subunit at specific serine residues (4, 40, 47).
In the present study, the murine monocyte/macrophage cell line RAW 264.7 and primary peritoneal macrophages were studied for secretion of different chemokine species in response to SP. Molecular mechanisms and signaling transduction, particularly the cross talk between MAPK and NF-B pathways, were investigated for the chemokine response. The findings that neuropeptide induces macrophages to release chemokines and elucidation of key signaling molecules involved help clarify our understanding of the interplay between the nervous and immune systems and provide the basis for neuronal therapeutic intervention in inflammatory and immune-mediated diseases.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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B inhibitor Bay 11-7082, ERK1/2 inhibitor PD 98,059, and the p38 MAPK inhibitor SB 203580 were obtained from Calbiochem (San Diego, CA). DMEM, heat-inactivated FBS, Novex 10% Tris-glycine polyacrylamide gels, and Novex transfer buffer were obtained from Invitrogen (Gaithersburg, MD). Phospho-IB (Ser32), IB, phospho-NF-B p65 (Ser276), phospho-p44/42 MAPK (phospho-ERK1/2), p44/42 MAPK (ERK1/2), phospho-p38 MAPK, p38 MAPK, phospho-JNK, and JNK antibodies were purchased from Cell Signaling Technology (Beverly, MA). Hypoxanthine-guanine phosphoribosyltransferase antibody (HPRT) and horseradish peroxidase (HRP)-conjugated goat anti-rabbit IgG secondary antibody were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Polyclonal anti-p65 antibody was purchased from Serotec (Raleigh, NC). SuperSignal West Pico chemiluminescent substrate, X-ray films, the biotin 3'-end DNA labeling kit, and the LightShift chemiluminescent EMSA kit were obtained from Pierce (Rockford, IL). Zeta-Probe cationized nylon membrane and the Bradford protein assay kit were obtained from Bio-Rad Laboratories (Hercules, CA). The nuclear extract kit and TransAM NF-B p65 transcription factor assay kit were obtained from Active Motif (Carlsbad, CA). Murine macrophage inflammatory protein (MIP)-2 and monocyte chemoattractant protein (MCP)-1 Duoset ELISA kits were obtained from R&D Systems (Minneapolis, MN).
Cell culture and treatment.
RAW 264.7 cells were grown in DMEM supplemented with 10% (vol/vol) FBS, 2 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin and were maintained at 37°C in a humidified atmosphere containing 5% CO2. For treatments, cells were seeded onto six-well plates and allowed to grow overnight to 70–80% confluence. Cells were deprived of serum for at least 2 h before experiments. SP, CP96,345, and L703,606 were dissolved in sterile saline (0.9%). L659,877 and all inhibitors were dissolved in DMSO and diluted in serum-free DMEM medium to the desired concentrations such that the final DMSO concentration was <0.1%. SP stimulation of cells was carried out at cell culture conditions. In some experiments, cells were pretreated with CP96,345, L703,606, or L659,877 (1 µM) for 10 min or with NF-B inhibitor Bay 11-7082, ERK1/2 inhibitor PD 98,059, or p38 MAPK inhibitor SB 203580 (at the concentrations indicated) for 1 h before addition of SP.
Isolation of peritoneal macrophages. Resident peritoneal macrophages were isolated as described previously with modifications (5). Briefly, closed peritoneal lavage was performed on anesthetized mice using 10 ml of ice-cold PBS. Peritoneal exudate cells were collected, washed once with PBS, and resuspended in supplemented DMEM. Peritoneal macrophages were allowed to adhere in six-well plates at 37°C in a humidified 5% CO2 incubator for 2 h, after which nonadherent contaminating cells were removed and the primary macrophage cultures were maintained for an additional 2 h before they were subjected to SP treatment and subsequent experiments. The preparations routinely contain >95% macrophages, as verified by microscopic examination with Turk's staining.
ELISA. Chemokine concentration in the media of cultured RAW 264.7 cells was determined using the murine MIP-2 and MCP-1 Duoset ELISA kits according to the instructions of the manufacturer. Samples were run in triplicate for each condition in three independent experiments. Absorbance was measured at 450 nm by a microplate reader (Tecan Systems, San Jose, CA). Results are expressed as picograms per milliliter of each chemokine.
Whole cell lysate preparation and Western blot analysis.
At the end of their designated treatment, cells were lysed with chilled radioimmunoprecipitation assay lysis buffer supplemented with protease inhibitor cocktail and phosphatase inhibitor cocktails. Protein concentrations were determined using the Bradford protein assay. Protein samples (50–100 µg) were separated on Novex 10% Tris-glycine polyacrylamide gels and transferred onto polyvinylidene difluoride membranes by electroblotting in Novex transfer buffer containing 20% (vol/vol) methanol. Membranes were then washed, blocked, and probed overnight with rabbit phospho-IB (Ser32), IB, phospho-NF-B p65 (Ser276), phospho-p44/42 MAPK (phospho-ERK1/2), p44/42 MAPK (ERK1/2), phospho-p38 MAPK, p38 MAPK, phospho-JNK, and JNK antibodies (1:1,000 dilution) or HPRT (1:2,000), followed by the HRP-conjugated goat anti-rabbit IgG secondary antibody (1:2,000) for 2 h. Membranes were washed and then incubated in SuperSignal West Pico chemiluminescent substrate before exposure to X-ray films. The intensity of bands was quantified using LabWorks Image Analysis software (UVP). HPRT was used as the housekeeping protein.
Nuclear extract preparation.
Nuclear extracts were prepared at various time points after treatment for subsequent NF-B DNA binding activity assay or EMSA. Cell nuclear fractions were extracted using a nuclear extract kit. Briefly, cells were washed, collected in ice-cold PBS in the presence of phosphatase inhibitors, and then centrifuged at 300 g for 5 min. Cell pellets were resuspended in a hypotonic buffer, treated with detergent, and centrifuged at 14,000 g for 30 s. After collection of the cytoplasmic fraction, the nuclei were lysed and nuclear proteins solubilized in lysis buffer containing proteasome inhibitors. Protein concentrations were determined using the Bradford protein assay.
NF-B DNA binding activity assay.
NF-B DNA binding activity was analyzed using the TransAM NF-B p65 transcription factor assay kit following the manufacturer's instructions. Briefly, nuclear extract (5 µg) were incubated in the 96-well plate coated with oligonucleotide containing the NF-B consensus binding sequence (5'-GGGACTTTCC-3'). Bound NF-B p65 were then detected with a specific primary antibody. A HRP-conjugated secondary antibody was then used to detect the bound primary antibody and provided the basis for colorimetric quantification. The enzymatic product was measured at 450 nm with a microplate reader (Tecan Systems). The specificity of this assay was tested by addition of the wild-type or mutated NF-B consensus oligonucleotide into the competitive or mutated competitive control wells before the addition of nuclear extracts.
EMSA.
Complementary NF-B consensus oligonucleotides (5'-AGTTGAGGGGACTTTCCCAGGC-3' and 5'-GCCTGGGAAAGTCCCCTCAACT-3') were synthesized by 1st BASE The oligos were end-labeled with biotin separately using the biotin 3'-end DNA labeling kit and then annealed by heating to 95°C for 2 min followed by slow cooling to room temperature. Probes were stored at –20°C until use. EMSA was performed with the LightShift chemiluminescent EMSA kit following the manufacturer's instructions. Briefly, DNA binding reactions were set up by incubating 10 µg of nuclear extract and 20 fmol of biotin-labeled probe together with 1 µg of poly(dI-dC) for 20 min at room temperature in 20 µl of binding buffer (10 mM Tris, pH 7.5, 50 mM KCl, and 1 mM DTT). For competition or supershift assays, unlabeled double-stranded NF-B consensus oligonucleotides or polyclonal anti-p65 antibodies were added to the reaction mixture before addition of the labeled probes. Samples were fractionated on native 6% polyacrylamide gels in 0.5x Tris-borate-EDTA buffer and then transferred onto Zeta-Probe cationized nylon membranes. After being cross-linked by a UV-light cross-linker (Spectronics), the biotin-labeled DNA on the membranes was detected by chemiluminescence. Band shifts were visualized by exposure to X-ray films.
Statistical analysis. Data are means ± SD. Statistical analyses were performed using independent t-test or, when multiple comparisons were made, one-way ANOVA with post hoc Tukey's test using SPSS version 13.0 (Chicago, IL). A P value <0.05 was considered a statistically significant difference.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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, MIP-1β, and RANTES (regulated on activation normal T-expressed and presumably secreted); data of the later 3 not shown], MIP-2 and MCP-1 are the major chemokines released by RAW 264.7 macrophages in response to SP stimulation. A gradual increase in the baseline levels of MIP-2 and MCP-1 (released by resting cells) was observed over time, suggesting the two chemokines were spontaneously secreted by the cells. Treatment of cells with SP further enhanced the secretion. Both doses of SP (10 and 100 nM) caused a significant elevation of MIP-2 and MCP-1 release after 4 h of incubation up to 24 h. No significant difference between these two doses of SP in inducing chemokine production was noted (Fig. 1, A and B).
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Whether SP could stimulate chemokine release in primary peritoneal macrophages was also examined. Significant increase in MIP-2 and MCP-1 production was observed in isolated primary peritoneal macrophages following stimulation of 100 nM SP for 24 h (Fig. 2, A and B). Stimulation with lower doses of SP or for shorter durations did not show a significant effect on chemokine production (data not shown). Our results indicate that although sensitivities to the neuropeptide differ, both the RAW 264.7 cell line and primary macrophages secrete chemokines in response to SP stimulation.
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B but not AP-1 activity in RAW 264.7 cells via NK-1 receptor.
Next, we sought to identify the transcription factors that take part in SP-stimulated chemokine synthesis. NF-B and AP-1 transcription factors, known to be activated by SP to promote chemokine gene transcription, were examined. Cells were treated with SP (10 nM) for 0, 15, 30, or 60 min. Nuclear fractions from cells were extracted and assayed for NF-B p65 or AP-1 DNA binding activity. The results showed a constitutive NF-B activity in the cells that may account for the spontaneous chemokine production and secretion. Treatment of SP caused a notable increase in the basal activity of NF-B p65, indicating its role in SP-induced transcriptional pathway in RAW 264.7 macrophages. Analysis of the kinetics of the induction showed that the DNA binding activity of NF-B p65 increased after 15 min of SP incubation and reached a peak at 30 min, followed by a decrease at 60 min (Fig. 4A). In contrast, the activity of AP-1 remained unaffected by SP (Fig. 4B). A dose-dependent experiment showed that the maximum p65 activity was observed at concentrations from 1 nM to 1 µM SP (Fig. 4C). SP-induced increase in NF-B activity was inhibited by pretreatment with NK-1 receptor antagonists, suggesting that SP-induced NF-B activation pathways emanated from this receptor (Fig. 4D).
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B via the classic pathway and posttranslational phosphorylation of p65 at Ser276 in RAW 264.7 macrophages.
The well-characterized classic pathway of NF-B activation involves phosphorylation of NF-B inhibitory protein IB and subsequent proteasomal degradation leading to NF-B nuclear translocation. We next investigated whether this pathway is induced by SP in RAW 264.7 cells. Also, because activation of NF-B involves transactivation through posttranslation modifications of the p65 subunit, we examined the phosphorylation status of p65 at Ser276 using the specific antibody. Whole cell lysates were prepared at various time points following SP stimulation and analyzed by Western blotting for phospho-IB, IB, and phospho(Ser276)-p65 protein expression. In a separate experiment, cytosolic and nuclear fractions of the cells were prepared and immunoblotted for phospho(Ser276)-p65 levels. The results indicated that phospho-IB protein became significantly elevated as early as 5–15 min following SP stimulation. The protein level further increased until the 30-min time point and gradually decreased thereafter to the baseline level at 120 min (Fig. 5, A and B). Total IB protein levels were significantly decreased after 15 min of SP treatment and were subsequently replenished after 30 min (Fig. 5, A–C). Nuclear translocation of activated NF-B was evidenced by the marked increase of phospho-p65 protein in the nuclear fractions of the cells. Cytosolic phospho-p65 levels were first slightly decreased with the translocation and accumulation of the protein into the nuclei but were subsequently restored (Fig. 5, D and E).
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B activation abolishes SP-induced chemokine production in RAW 264.7 macrophages.
To confirm that SP stimulates chemokine release through the NF-B signal transduction pathway, we examined the effect of Bay 11-7082, a selective and irreversible inhibitor of NF-B, on SP-elicited chemokine production by macrophages. Cells were preincubated with Bay 11-7082 (1, 10, or 30 µM) for 1 h before being treated with SP (10 nM) for 4 h. As shown in Fig. 6, A and B, Bay 11-7082 dose-dependently inhibited induction of MIP-2 and MCP-1 production by SP. The inhibitory effect was significant with 10 µM Bay 11-7082. At 30 µM, Bay 11-7082 almost completely abolished SP-stimulated chemokine upregulation.
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B activation.
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B DNA binding activity and phosphorylation are differentially regulated by ERK1/2 and p38 MAPK.
We further examined whether the inhibitory effects of MAPK-selective inhibitors on chemokine production were mediated by NF-B. The possible cross talk between NF-B and MAPK pathways was studied by examining the effect of PD 98,059 and SB 203580 on DNA binding activity of NF-B after SP stimulation. Both NF-B DNA binding activity assay and EMSA demonstrated that inhibition of p38 MAPK significantly blocked SP-induced NF-B DNA binding activity. However, there was no significant alteration of SP-induced NF-B activity when cells were pretreated with the ERK1/2 inhibitor PD 98,059 (Fig. 9, A and B). The results suggest a role for p38 MAPK but not ERK in regulating DNA binding activity of NF-B.
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B with MAPKs, we studied the inhibitor effects on Ser276 phosphorylation of p65. Western blotting results indicated that pretreatment with both inhibitors significantly diminished nuclear levels of phospho(Ser276)-p65 protein. The effects were similar to pretreatment with the NK-1 receptor antagonist L703,606 (Fig. 10, A and B). Since phosphorylation of p65 at this residue is associated with coactivator recruitment to the NF-B transcription complex and enhanced transactivational activity of the protein, ERK1/2 and p38 MAPK may be implicated in the posttranslational phosphorylation and regulation of transactivation potential of the p65 subunit.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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As cellular models, we used the mouse monocyte/macrophage cell line RAW 264.7 and freshly isolated primary peritoneal macrophages, which are known to express functional high-affinity tachykinin receptors (3, 27). We found that SP, at nanomolar concentrations, caused selective chemokine response in murine macrophages: secretion of some chemokines but not others. We examined a range of well-documented proinflammatory chemokines (MIP-2, MCP-1, MIP-1, MIP-1β, and RANTES) inducible in macrophages and involved in a number of immune and inflammatory conditions (9, 16, 24, 26, 37). Among those tested, MIP-2 and MCP-1 are the two chemokines inducible by SP. This selective chemokine release by macrophages may suggest the specific pathological role of SP in inflammation with these two chemokines involved.
We further investigated the mechanism controlling transcriptional activation of chemokine genes. The transcription factor NF-B, which plays a pivotal role in proinflammatory gene induction, was studied. Three mechanisms of NF-B activation have been described: the classic pathway dependent on NF-B inhibitory protein IB degradation and two atypical pathways, one through the processing of p100 and release of p52/RelB into the nucleus and the other through the phosphorylation of p65 at multiple serine sites by some protein kinases (29, 41). We observed a pronounced enhancement of NF-B DNA binding activity in macrophages after exposure to SP. SP in macrophages activated the classic NF-B pathway as evidenced by the phosphorylation and subsequent degradation of IB as well as nuclear translocation of phosphorylated NF-B p65. NF-B-chemokine response induced by SP emanated from the NK-1 receptor, since the NK-1 receptor antagonists blocked SP-enhanced NF-B activity and chemokine production. In addition to NF-B, SP was shown to activate AP-1 transcription factor in regulating chemokine gene expression in a cell-specific manner (22, 25, 34). However, we observed no increase in AP-1 activity in RAW 264.7 macrophages with SP stimulation. The transcriptional dependence of MIP-2 and MCP-1 on NF-B was confirmed with a specific NF-B inhibitor, Bay 11-7082. Bay 11-7082 selectively and irreversibly prevents IB phosphorylation, which disrupts NF-B function by sparing IB from proteasomal degradation, thereby permitting it to bind to and inactivate NF-B (33, 45). Pretreatment with Bay 11-7082 diminished the chemokine responses induced by SP, which reinforced NF-B as the main transcriptional regulator involved.
Next, we focused on the involvement of NF-B-activating kinase family, MAPKs, in the signaling cascade. Activation of three well-established MAPK subfamilies, ERK1/2, JNKs, and p38 MAPK, was examined. JNKs were not activated in the cells after SP treatment, which may partially account for the lack of AP-1 induction in the cells. In contrast to JNKs, both ERK1/2 and p38 MAPK were strongly activated by SP in a time-dependent manner. The time course of activation differed between the two MAPKs. Activation of ERK1/2 started at 5 min and was sustained until 30 min before decline. Activation of p38 MAPK was transient and more rapid, maximizing at 5 min and declining thereafter. Blocking these two MAPK pathways using their specific inhibitors almost completely inhibited SP-induced chemokine release from macrophages. To further define the mechanisms of MAPK regulation of chemokine production, we investigated the effects of the ERK1/2 and p38 MAPK inhibitors PD 98,059 and SB 203580, respectively, on NF-B DNA binding activity and phosphorylation of p65 subunit. Surprisingly, we observed differential effects of ERK1/2 and p38 MAPK inhibition on NF-B activity: PD 98,059 had no effect on NF-B DNA binding, whereas SB 203580 significantly reduced SP-induced NF-B activity. However, both PD 98,059 and SB 203580 significantly decreased the nuclear levels of Ser276-phosphorylated p65. The role of ERK1/2 and p38 MAPK in regulating NF-B activity varies in a stimulus- and cell type-specific manner. The finding that ERK1/2 control NF-B-dependent gene expression without affecting DNA binding has been supported by earlier studies (1, 12, 31, 39, 43). Our demonstration that SP induces Ser276 phosphorylation of NF-B p65 and its nuclear translocation represents one mechanism for SP-elicited NF-B activation and chemokine induction in macrophages. Posttranslational modifications of p65 subunit have been proposed to constitute a layer of NF-B activity regulation (15, 43). Phosphorylation of p65 (RelA) subunit at Ser276 is associated with recruitment of transcriptional coactivator p300/CBP to the NF-B transcriptional complex and enhanced transactivation ability of NF-B (14, 28, 40, 46, 47). Protein kinase A and stress-activated kinase 1 (MSK1) are the two kinases known to directly phosphorylate p65 at Ser276 (40, 47). MSK1 has been shown to be a kinase substrate for ERK1/2 and p38 MAPK and therefore may represent the interaction point between NF-B and MAPK pathways (10, 19). Our results suggest that SP-induced ERK1/2 signaling pathway controls NF-B-dependent chemokine expression by regulating the transactivation activity of p65 subunit without interfering with DNA binding, whereas p38 MAPK controls both phosphorylation of NF-B p65 and the DNA binding activity of the protein. Further studies are required to elucidate the exact molecular events and intermediaries that lead to p65 transactivation enhancement and the resultant chemokine induction by SP.
Taking these data together, as summarized in Fig. 11, the current study demonstrates that SP induces selective chemokine production in murine macrophages. Cross talk between MAPK (ERK1/2 and p38 MAPK) and NF-B pathways is implicated in the chemokine response. Our findings further extend the importance of macrophages in SP-mediated neurogenic inflammatory conditions. Elucidation of the key signaling pathways and molecules involved may have profound implications in controlling the conditions.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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