Department of Surgery, School of Medicine, Wayne State University and John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan
Submitted 9 November 2004 ; accepted in final form 27 December 2004
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ABSTRACT |
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force; inflammation; infection; leukocyte; mechanotransduction; signal transduction
Recent reports suggest that physical forces such as extracellular pressure and repetitive strain may alter other aspects of macrophage functions. Pressure (40130 mmHg) increases monocyte migration in a dose-dependent manner and enhances scavenger receptor expression in macrophages. Macrophages produce proinflammatory cytokines in response to very high cyclic pressure (>1,000 mmHg), the combination of cyclic strain and 75 mmHg pressure, or high pressure (>70 mmHg) combined with stimulation by endotoxin. Increased pressure (4090 mmHg), but not cyclic strain, has also been shown to increase the uptake of aggregated IgG by the mouse macrophage J774.16 cell line (46, 47, 52). The mechanisms or intracellular signals responsible for this effect have not been defined.
However, these pressures are higher than are often observed in edematous tissue. We therefore examined the effects of constant low pressure (20 mmHg) on macrophage phagocytosis by studying human primary isolated peripheral monocytes and monocyte-derived macrophages (MDM) as well as PMA-differentiated (macrophage-like) human THP-1 monocytic cells in which we had previously described pressure-increased phagocytosis (67).
p38 MAPK is activated by microbial phagocytosis in phagocytic cells (50, 58) and in response to mechanical stimuli, such as pressure and strain in some other types of cells (2, 4, 44, 75, 76, 80), and activates downstream kinases mediating inflammatory reactions (3, 55, 72). In this study, we examined the involvement of p38 MAPK activation by pressure in THP-1 macrophage and human monocyte phagocytosis. In further studies, we explored the relationship between the previously described inhibition of FAK and ERK by pressure and the p38 MAPK activation by pressure that we now report. Although a relationship between FAK and ERK and integrin-mediated phagocytosis in macrophages has not previously been established, FAK and ERK are activated by integrin cross-linking after phagocytosis occurs (48, 61), and downregulation of the FAK-ERK signal partially mediates pressure-induced macrophage phagocytosis (67). We used the pharmacological inhibitor SB-203580 to probe the role of p38 MAPK in mediating the effect of pressure, as well as a specific small interfering RNA (siRNA) targeted to the p38 MAPK isoform.
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MATERIALS AND METHODS |
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Cells and cell cultures. The human monocytic cell line THP-1 was obtained from the American Type Culture Collection (Rockville, MD) and maintained in RPMI 1640 (GIBCO, Grand Island, NY) supplemented with 10% FBS (Sigma, St. Louis, MO), L-glutamine (200 mM), and 2-mercaptoethanol (5 x 105 M; Sigma). THP-1 cells (5 x 105 cells/35-mm dish) were differentiated by stimulation with PMA (50 ng/ml, final concentration) for 3 days to obtain a macrophage-like phenotype that closely resembles human MDM, as previously reported (5, 14, 74).
Peripheral venous blood was obtained from consenting healthy volunteers by a protocol approved by the Human Investigation Committee of Wayne State University School of Medicine and the John D. Dingell Veterans Affairs Medical Center. Peripheral blood mononuclear cells (PBMC) were isolated from heparinized venous blood by Ficoll-Hypaque density gradient sedimentation, as described previously (66, 68, 69). PBMC were suspended at a density of 1 x 107/ml in RPMI 1640 medium supplemented with 100 U/ml penicillin G, 2 mM L-glutamine, and 10% fresh autologous unheated human serum. One 100-µl droplet of cell suspension was plated in each well of a LabTek chamber. The chambers then were incubated for 60 min at 37°C. Nonadherent cells were washed off, and the monocyte monolayers were used for phagocytosis assays. MDM were prepared by culturing monocytes for 6 days in RPMI 1640 medium with 10% autologous unheated serum at 37°C in 5% CO2.
Pressure box model. Ambient pressure was controlled by an apparatus previously used in other studies (7, 67, 73, 80). Cells are placed in an air-tight Lucite chamber with gas inlet and outlet valves, thumb screws, and an O-ring to achieve an airtight seal and a pressure manometer to monitor inside pressure. The box was prewarmed to 37°C for 1 h before each study to prevent fluctuations in internal pressure caused by temperature shifts of the pressurizing gas; the appropriate target pressure was achieved within 1 min. Temperature and pressure were maintained within 2°C for temperature and 1.5 mmHg for pressure using this method, and the pH, osmolarity, and PO2 of the culture medium remained essentially the same over the course of the study (7).
Assay for phagocytosis. Fluorescence-labeled latex beads (2.0 µm) were opsonized with 10% unheated FBS for 60 min at 37°C before the experiments. PMA (1 x 106)-differentiated THP-1 in 1 ml of tissue culture medium supplemented with 10% FBS in a 35-mm petri dish, 1 x 105 primary isolated human monocyte monolayers, or MDM in 500 µl of RPMI 1640 with 10% autologous unheated serum in a LabTek chamber were mixed with opsonized latex beads at a multiplicity ratio of 1:5 and incubated for 2 h at 37°C. One set of dishes was placed in a calibrated pressure box. The pressure inside the pressure box was set at 20 mmHg, and the pressure box was placed inside an incubator at 37°C and monitored every 15 min. The second set of dishes was placed inside the same incubator but under ambient pressure conditions. After 2 h, macrophage monolayers were washed vigorously with PBS to remove extracellular beads, fixed with methanol for 10 min, and then counterstained with methylene blue. The number of intracellular latex particles was determined by counting fluorescent beads within cells under a fluorescence microscope. Data were expressed as percent phagocytosis, calculated as the total number of cells with at least one bead as a percentage of the total number of cells counted.
Western immunoblotting. THP-1 macrophages were incubated under ambient or increased pressure (20 mmHg) conditions for 30 min, rinsed one time with cold PBS, and lysed with lysing buffer. Protein concentrations in cell lysates were measured using the bicinchoninic acid protein assay reagent (Pierce, Rockford, IL). Equal amounts of protein were loaded in each lane. Cell lysates were resolved under reducing conditions by 10% SDS-PAGE and then transferred to nitrocellulose membranes. After being blocked with 5% BSA in Tris-buffered saline (TBS) with 0.1% Tween 20, the membranes were incubated with antibodies against activated or total forms of protein overnight at 4°C, washed three times with 0.1% Tween 20-TBS, and then incubated for 60 min with 2,000:1 peroxidase-conjugated anti-rabbit IgG. The membrane-bound peroxidase activity was detected using ECL Plus Western Blotting Detection kits (Amersham, Arlington Heights, IL). Chemiluminescent images were captured and analyzed using a Kodak Digital Science Image Station 440CF. All blots were studied within the linear range of exposure.
Transfection of siRNA.
To inhibit p38 MAPK or FAK protein expression, THP-1 cells were transfected with siRNA. The siRNA targeted to p38 MAPK was purchased from Upstate USA (catalog no. M-003556). The siRNA duplex targeted to FAK, 5'-GCAUGUGGCCUGCUAUGGAdTdT/dTdTCGUACACCGGACGAUACCU-5', directed toward the mRNA target, 5'-AAGCAUGUGGCCUGCUAUGGA-3', has been previously described (67, 73) and was synthesized by Dharmacon (Lafayette, CO). siRNA targeted to p38 MAPK and a scrambled RNA duplex used as a control were purchased from Dharmacon. THP-1 cells (4 x 105 cells/60-mm petri dish) were stimulated with PMA (50 ng/ml) for 2 days before transfection. Transfection of duplex siRNAs were performed using Oligofectamine (GIBCO, Gaithersburg, MD) according to the manufacturer's protocol. After transfection (24 h), cells were used for Western analysis and for assays of phagocytosis. Transfection efficacy, measured by transfecting Cy3-conjugated siRNA targeted to luciferase (Upstate USA), was 9097% (67).
Statistical analysis. The significance of differences between groups was calculated by the Student's t-test or paired t-test as appropriate. Confidence (95%) was set a priori as the desired level of statistical significance.
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RESULTS |
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Effect of p38 MAPK inhibition on FAK and ERK. We next examined the converse, whether the effect of pressure on p38 MAPK activation might modulate the inhibition of FAK and ERK signals previously shown to contribute to the pressure effect. In initial studies, p38 MAPK was inhibited by pretreatment with 20 µM SB-203580 for 60 min before exposure to pressure. FAK and ERK activation by pressure were then examined. Pretreatment of THP-1 macrophages with SB-203580 did not alter total FAK or ERK protein expression (see blots on bottom in Fig. 5, A and B). SB-203580 pretreatment significantly increased ERK phosphorylation and prevented the inhibition of ERK phosphorylation by pressure (Fig. 5A). FAK-Y397 phosphorylation was reduced by pressure in DMSO vehicle control cells and was not affected by SB-203580 pretreatment under ambient pressure. However, the inhibition of FAK-Y397 phosphorylation by pressure was not observed in THP-1 macrophages pretreated with SB-203580 (Fig. 5B). These data raised the possibility that p38 MAPK might influence the downregulation of ERK and FAK activation by pressure.
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DISCUSSION |
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Normal interstitial tissue pressure in humans is 2030 mmHg and generally decreases in the setting of acute infection and inflammation (17, 19, 51, 85). Extracellular pressures within inflamed or infected tissues can vary substantially. For example, infection or edema in closed compartments may increase tissue pressure by 580 mmHg (8, 64, 65). However, the interstitial or extracellular pressure generally decreases in infected or inflamed tissue lacking such special circumstances (13, 31, 54, 85). Indeed, edema formation in unconstrained inflamed or infected tissues may actually be associated with decreases in connective tissue interstitial fluid pressures by as much as 150 mmHg (85). If the tissue pressure decreases by >10 mmHg or increases over 60 mmHg, pain and cell damage may follow (17, 51). Invasive fungal pathogens such as Pythium insidiosum, a potentially lethal infectious pathogen in humans, exert pressures as high as 2,000 mmHg (60). Macrophages moving from the capillaries into inflamed tissue are also exposed to capillary pressure elevations. In patients with colonic inflammatory bowel disease, for instance, colonic blood flow is increased two- to sixfold, causing capillary pressure to rise by 1040 mmHg (18, 24). Activation or inhibition of macrophages by changes in extracellular pressure may therefore affect macrophage function in such settings.
Monocytes and macrophages play a critical role in wound healing, infection, and inflammation (1, 57) and are sensitive to biomechanical stimuli, including cyclic strain, shear, and pressure, although forces of a different nature or magnitude may yield different effects, particularly at different end points (32, 46, 47, 52, 59, 67, 70). Exposure of human MDM to cyclic high pressure (2501000 mmHg) induces cytokine production (49). We have reported that a constant lower pressure (20 mmHg), which may be more relevant to the cell biology of inflamed tissue, enhances THP-1 macrophage phagocytosis (67), and our current work shows that primary human monocytes behave similarly. Phagocytosis of particles activates several tyrosine kinases that might stimulate further phosphorylation of tyrosine kinases associated with phagosomes in macrophages. However, tyrosine kinases within the cells may also conversely influence the uptake of particles by macrophages.
p38 MAPKs regulate cell growth, cell differentiation, cell activation, and cell survival and respond to inflammation and stress stimuli. In macrophages, p38 MAPKs are activated by cellular stress and microbial phagocytosis (63, 84). However, a role of p38 MAPK in regulating macrophage phagocytosis has not previously been elucidated. Li et al. (41) have reported that p38 MAPK signaling is required for osteoclast differentiation but found that inhibition of p38 MAPK does not affect phagocytosis or cytokine production by murine bone marrow macrophages. Conversely, Hsu et al. (22) have reported that phagocytosis enhanced by polysaccharide from Ganoderma lucidum in neutrophils is mediated by p38 MAPK, phosphatidylinositol 3-kinase, and protein kinase C (22). Mechanical stimuli caused by stretch or pressure have been reported to activate p38 MAPK in some types of cells (2, 4, 44, 75, 76, 80). Our current data suggest that increased p38 MAPK activation in response to extracellular pressure leads to pressure-induced phagocytosis by THP-1 macrophages as well as in primary isolated human peripheral monocytes.
The p38 MAPK family includes four distinct isoforms [p38 MAPK (SAPK2a; see Ref. 37), p38 MAPK
(SAPK2b; see Refs. 28 and 71), p38 MAPK
(SAPK3/ERK6; see Refs. 36 and 42), and p38 MAPK
(SAPK4; see Refs. 29 and 82)] with distinct cellular distribution patterns in mammalian cells. p38 MAPK
and p38 MAPK
are widely expressed in various cell types and tissues, whereas expression of p38 MAPK
and p38 MAPK
is more restricted (20, 36, 42). Monocytes express predominantly p38 MAPK
protein. p38 MAPK
mRNA has been identified in monocytes and macrophages without detectable levels of p38 MAPK
protein (20). Monocytes do not express p38 MAPK
or p38 MAPK
. After differentiation to macrophages, these cells begin to express p38 MAPK
(20). PMA-differentiated THP-1 macrophages express p38 MAPK
and p38 MAPK
. In the current study, we chose the p38 MAPK
isoform as the target gene for siRNA, because the pressure effect was abolished by SB-203580, which inhibits p38 MAPK
and -
, and also because SB-203580 also abrogated pressure-induced phagocytosis in human peripheral monocytes, which predominantly express p38 MAPK
and undetectable levels of p38 MAPK
protein and do not express the p38 MAPK
or -
isoforms. Our results suggest that p38 MAPK
activation mediates THP-1 macrophage and human peripheral monocyte phagocytosis induced by extracellular pressure. This conclusion is supported by our observations that pressure-induced phagocytosis was prevented by pretreatment with SB-203580 or by transfection with p38 MAPK
siRNA (21). Furthermore, the augmentation of p38 MAPK phosphorylation by pressure in THP-1 cells transfected with p38 MAPK
siRNA was attenuated. These data suggest that p38 MAPK activation by pressure might mediate pressure-induced phagocytosis by THP-1 macrophages and human peripheral monocytes.
ERK, another MAPK, is activated by cross-linking of integrins and phagocytosis of particle antigens in macrophages, and ERK activation subsequently influences cytokine expression, cell survival, and control of intracellular pathogen growth. ERK is typically activated by mechanical forces in such other types of cells as osteoblasts (27), smooth muscle cells (34, 75), skeletal muscle fibers (33), intestinal epithelial cells (40, 77), cardiac fibroblasts (81), and cardiac myocytes (45). However, ERK is not activated by pressure in malignant colonocytes in suspension (73) or in rat neonatal cardiac fibroblasts expressing prominent stress fibers and high basal levels of smooth muscle actin (81). Indeed, we previously reported that ERK is actually inhibited in response to increased extracellular pressure in THP-1 cells, together with enhanced phagocytosis (67). ERK blockade mimicked the pressure effect on phagocytosis and substantially attenuated the further stimulation of phagocytosis by pressure.
Cross talk between p38 MAPK and ERK may be important for regulation of cell function, although this has not previously been addressed in human macrophages. We therefore performed experiments to analyze the potential relationship between p38 MAPK and ERK in our system. We found that inhibition of ERK by PD-98059 did not affect basal p38 MAPK phosphorylation or p38 MAPK phosphorylation in response to pressure. This contrasts with the report by Xiao et al. (87), who demonstrated that LPS-induced p38 MAPK phosphorylation is enhanced by ERK inhibition by PD-98059 in the murine macrophage RAW cell line. Xiao et al. did not assess the effects of PD-98059 on basal p38 phosphorylation, however. Taken together, our results and those of Xiao et al. suggest that pressure may modulate p38 phosphorylation by a different pathway than LPS (87).
We also observed that inhibition of p38 MAPK by SB-203580 or by p38 MAPK siRNA significantly increased basal ERK phosphorylation in THP-1 macrophages. This is consistent with the previous report by Xiao et al. (87). Furthermore, we also found that p38 MAPK inhibition abolished the inhibition of ERK activation by pressure. In contrast, inhibition of ERK by PD-98050 affected neither basal p38 MAPK activation nor p38 MAPK activation by pressure in THP-1 macrophages. These results suggest that activation of p38 MAPK by pressure may lead to subsequent downstream inhibition of ERK activation.
FAK is a multifunctional tyrosine kinase associated with signaling triggered by integrin cross-linking and expressed by a variety of cell types. FAK protein expression in THP-1 cells is induced after stimulation with PMA and differentiated into macrophage-like cells (67). Activation of FAK by mechanical forces such as pressure has been reported in other types of cells, including colonic cancer cells (40, 73), NIH 3T3 fibroblasts (78), and cardiomyocytes (62, 86), often in parallel with p38 MAPK activation (4, 23, 40, 80). In our system, however, pressure increased p38 MAPK activation but inhibited activation of FAK-Y397 in PMA-differentiated THP-1 macrophages, leading to enhanced latex bead uptake. Inhibition of FAK by transfection with siRNA targeted to FAK also increased THP-1 macrophage phagocytosis.
The relationship between FAK and p38 MAPK in macrophages is poorly understood. Our group has previously shown that a higher amount of activated p38 MAPK in nonadherent SW620 colon cancer cells is associated with decreased FAK-Y397 phosphorylation, suggesting that the cross talk between FAK and p38 MAPK might regulate colon cancer cell adhesion and cell survival (80). Aikawa et al. (4) have reported that inhibition of FAK activation by phosphatase and tensin homolog deleted on chromosome 10 suppresses mechanical stretch-induced p38 MAPK activation in cardiac myocytes and that FAK activation might control p38 MAPK activation. In our current study, we observed that blocking p38 MAPK activity by SB-203580 prevented the inhibition of FAK-Y397 phosphorylation by pressure. On the other hand, pressure-induced inhibition of FAK-Y397 phosphorylation was not affected when p38 MAPK was inhibited by transfection with siRNA targeted to p38 MAPK. These differences in p38 MAPK inhibition by SB-203580 treatment and by p38 MAPK
siRNA transfection may be because of differences in the specificity of the experimental systems. siRNA targeting to p38 MAPK
specifically silences p38 MAPK
gene expression and would be expected to exhibit higher specificity than the chemical inhibitor. Although SB-203580 is widely employed as a specific p38 MAPK inhibitor, several studies have reported that SB-203580 possessed some other biological activity besides inhibiting p38 MAPK activity. These have included influencing Raf activation, activation of ERK, inhibition of JNK, and blocking Akt phosphorylation (9, 12, 15, 35, 90). Such nonspecific biological activities might influence pressure-associated changes in FAK-Y397 phosphorylation independent of pressure activation of macrophage p38.
Furthermore, basal p38 MAPK activation in THP-1 macrophages transfected with FAK siRNA did not differ from p38 MAPK activation in cells transfected with scrambled siRNA. However, the enhancement of p38 MAPK activation by pressure was attenuated in THP-1 macrophages transfected with FAK siRNA. These data suggest that the cross talk between p38 MAPK activation and inhibition of FAK-Y397 phosphorylation by pressure might regulate downstream ERK activation, leading to macrophage phagocytosis.
Taken together with our previous work (67), these data suggest that decreased FAK and ERK activity and increased p38 MAPK activity are all involved in the mediation of pressure-stimulated phagocytosis. We previously demonstrated that FAK appeared upstream of ERK in this pathway. The present results suggest that FAK inhibition by pressure is also upstream of p38 MAPK
stimulation by pressure and that p38 activity by pressure is upstream of ERK inhibition by pressure. Whether the FAK effect on ERK occurs solely via p38 MAPK modulation or whether FAK also affects ERK by a p38 MAPK-independent pathway awaits further investigation.
Although these investigations have begun to trace a pattern of intracellular signals by which macrophages may respond to increased extracellular pressure, the mechanism by which this change in extracellular pressure is initially sensed by the macrophage is not yet known. Extrapolation from studies and hypotheses in other cell types suggests that different cell types may sense various physical forces by several competing or complementary mechanisms. These have included tensegrity-type mechanotransduction by the cytoskeleton itself (25, 26), alterations in the activity of membrane ion channels (6, 16, 88), activation of GTP-binding proteins (30), and effects at the level of integrin-mediated cell-matrix interactions (89). Which one or more of these mechanisms may contribute to macrophage pressure sensing awaits elucidation.
There are clearly many differences between macrophage phagocytosis in vitro and immune surveillance in vivo, and p38 modulation also has the potential to affect other aspects of human biology and pathobiology. However, RWJ-67657, BIRB 796 BS, and SB-242235 are experimental drugs that have been used to inhibit p38 MAPK activity in preclinical studies and in an animal model of rat and monkey (10, 11, 56, 83). In the future, it is possible that drugs such as these might be useful to modulate p38 MAPK activity in macrophages to promote phagocytosis, but this possibility awaits substantial further study as well as the elucidation of possible side effects.
In summary, these results demonstrate that constant 20 mmHg pressure increases phagocytosis by primary isolated human monocytes and MDM, as well as in THP-1 macrophages, and that p38 MAPK activation by pressure contributes to the enhancement of monocyte/macrophage phagocytosis. Furthermore, cross talk between activation of p38 MAPK
and inhibition of FAK-Y397 phosphorylation by pressure may modulate the pressure-induced phagocytosis in THP-1 macrophages and human primary monocytes by regulating ERK phosphorylation.
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ACKNOWLEDGMENTS |
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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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