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(Journal of Leukocyte Biology. 2002;71:223-230.)
© 2002 by Society for Leukocyte Biology

Monocyte cell adhesion induced by a human aminoacyl-tRNA synthetase-associated factor, p43: identification of the related adhesion molecules and signal pathways

National Creative Research Initiatives Center for ARS Network, College of Pharmacy, Seoul National University, Korea

Correspondence: Sunghoon Kim, National Creative Research Initiatives Center for ARS Network, College of Pharmacy, Seoul National University, San 56-1, Shillim-dong, Kwanak-ku, Seoul, 151-742, Korea. E-mail: sungkim{at}snu.ac.kr

	ABSTRACT

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An aminoacyl-tRNA synthetase-associated factor, p43, was recently shown to be secreted to induce a proinflammatory response. Because a proinflammatory response involves the cell-cell adhesion between endothelial and immune cells, we first examined the mechanism of p43-induced cell-cell adhesion of myelomonocytic leukemia cells. Intercellular adhesion molecule-1 (ICAM-1) was up-regulated by p43 and mediated p43-induced cell-cell adhesion via the interaction with LFA-1 or Mac-1. We also investigated p43-stimulated signaling pathways involved in the homotypic THP-1 cell adhesion. Because the specific inhibitors for PI3-K (phosphatidylinositol 3-kinase), ERK (extracellular signal-regulating kinase), and p38 MAPK (mitogen-activated protein kinase) blocked p43-stimulated ICAM-1 expression and homotypic THP-1 cell adhesion, these kinases were responsible for p43-induced cell-cell adhesion. p43-Dependent activation of ERK was inhibited by PI3-K inhibitors, and the activation of p38 MAPK was not. Thus, the results of this work suggest that p43 should induce cell-cell adhesion via the PI3-K/ERK- and p38 MAPK-dependent up-regulation of ICAM-1.

Key Words: intercellular adhesion molecule-1 • mitogen-activated protein kinase • cell-cell adhesion • integrin ß₂

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
EMAP II (endothelial monocyte-activating polypeptide II) was first isolated from the supernatant of the cultured murine fibrosarcoma [¹ ] and functions as a novel cytokine inducing a proinflammatory response [² ]. It is expressed prominently in macrophages and monocytes located in inflammatory autoimmune lesions of the rat central nervous system [³ ] and thus believed to activate monocytes and microglial cells in inflammatory lesion [⁴ ]. EMAP II also induces the increase in calcium concentration of the cytoplasm in mononuclear phagocytes and polymorphonuclear cells (PMNs), which activate and release myeloperoxidase [² ]. In addition, it up-regulates tumor necrosis factor (TNF), TNF receptor-1, tissue factor (TF), and P-selectin and E-selectin related to the inflammation [⁵ , ⁶ ]. These diverse functions of EMAP II imply its critical role in the inflammation processes.

EMAP II is equivalent to the C-terminal domain of p43, which is a noncatalytic protein associated with macromolecular aminoacyl-tRNA synthetase complex [⁷ ]. For this reason, EMAP II was thought to be a cleaved product of p43. However, we recently found that p43, but not EMAP II, is secreted from the intact cells to exert cytokine activities and induces various proinflammatory signaling molecules in the monocytic THP-1 cell [⁸ ]. Among p43-induced genes, expression of intercellular adhesion molecule-1 (ICAM-1) was more than tenfold increased by the treatment of p43.

ICAM-1 is a surface-adhesion molecule playing a role in lymphocyte extravasation by the mechanisms of cell-cell adhesion [⁹ ]. The homo- and heterotypic cell adhesions are involved in a variety of physiological and pathophysiological processes including inflammation and atherosclerosis [¹⁰ ]. ICAM-1 mediates cell-cell adhesion via its interaction with the activated lymphocyte function-associated antigen-1 (LFA-1) and/or Mac-1, called the integrin ß₂ family members [¹¹ , ¹² ]. The cell-cell adhesion is also induced by the increased level of ICAM-1 expression [^{13 14 15 16} ].

Mitogen-activated protein kinases (MAPKs) and other signaling molecules including phosphatidylinositol 3-kinase (PI3-K) are considered to play important roles in cell-cell adhesions [¹¹ , ¹⁷ ]. Because p43 stimulates the activity of nuclear factor-B (NF-B) and MAPK family members, extracellular signal-regulating kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK [⁸ ], we thought that these molecules might be involved in p43-induced expression of intercellular adhesion molecule-1 (ICAM-1) and cell adhesion. Here, we investigated whether p43-induced expression of ICAM-1 is actually responsible for homo- and heterotypic adhesion of monocytes and determined the related signal pathway.

	MATERIALS AND METHODS

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Cell culture and materials
THP-1 cells were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) and 50 µg/ml streptomycin and penicillin in a 5% CO₂ incubator at 37°C. Antibodies against phospho-ERK, phospho-p38, were purchased from New England Biolabs (Beverly, MA). Antiphosphotyrosine antibody was obtained from BD Transduction Laboratories (Franklin Lakes, NJ), and anti-PI3-K p85 antibody and anti-ICAM-1 antibody (sc-1511; for Western blot) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA).

Construction and purification of p43 deletions
The plasmids expressing p43-(1-312), p43-(1-147), and p43-(148-312) were described previously [¹⁸ ]. To construct p43-(1-108), pET28a (Novagen, Madison, WI) containing the full-length p43 was digested with Asp718 and SalI. The large fragment was treated with the Klenow fragment to fill up the DNA ends, and the resulting DNAs were religated. The DNA fragments coding for p43-(1-90), p43-(91-170), p43-(91-256), p43-(91-312), p43-(218-312), and p43-(257-312) regions were synthesized by polymerase chain reaction (PCR) with specific primer sets. (The primer sequences will be available upon request.) The specific PCR products were digested with EcoRI and XhoI and ligated into pET28a cut with the same enzymes.

Each of the full-length p43 and p43-deleted constructs was expressed as His-tag fusion protein in Escherichia coli BL21 (DE3) and purified by nickel affinity chromatography and Mono Q or S ion-exchange chromatography as described previously [¹⁸ ]. To remove lipopolysaccharide (LPS), the protein solution was dialyzed in pyrogen-free buffer (10 mM potassium phosphate buffer, pH 6.0, 100 mM NaCl). After dialysis, the protein was loaded to polymyxin resin (Bio-Rad, Hercules, CA), pre-equilibrated with the same buffer, incubated for 20 min, and eluted. The concentration of the residual LPS was below 20 pg/ml when determined using the Limulus Amebocyte Lysate QCL-1000 kit (Bio-Whittaker, Walkersville, MD).

Western blots
The cells treated with p43 were harvested by centrifugation at 600 g for 5 min and lysed with 0.25 ml lysis buffer [50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM vanadate, 1 mM dithiothreitol, 1.0% Triton X-100, and 0.1 mM phenylmethylsulfonyl fluoride (PMSF)]. For p38 MAPK assay, cells were lysed by sonication in radioimmune precipitation buffer (RIPA). The proteins in the lysates were resolved by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), transferred onto a polyvinylidene difluoride (PVDF) membrane (Millipore, Milford, MA), and probed with specific antibodies. The antibodies bound to specific proteins were reacted with the secondary antibody conjugated with horseradish peroxidase and then detected with an enhanced chemiluminescence substrate kit (Amersham, Arlington Heights, IL).

PI3-K assay
After THP-1 cells were treated with p43 (100 nM), the cells were harvested at various time points. Then the cells were lysed with PI3-K lysis buffer [15 mM Tris, pH 7.50, 130 mM NaCl, 1 mM MgCl₂, 1 mM CaCl₂, 10% glycerol, 1% Nonidet P-40 (NP-40), 5 mM sodium orthovanadate, and 0.1 mM PMSF]. The soluble lysates (500 µg) were then incubated with antibodies specific for the PI3-K subunit p85 for 3 h at 4°C, followed by additional incubation for 1 h with protein G-agarose beads (Gibco BRL-Life Technologies, Grand Island, NY). Then, the immune complex was washed four times with the PI3-K lysis buffer and resolved by 10% SDS-PAGE. Proteins on the gel were electrotransferred to a PVDF membrane (Millipore). The membranes were immunoblotted with antiphosphotyrosine antibody.

Homotypic cell-cell adhesion
THP-1 cells were inoculated at 2 x 10⁶ cells/ml in 24-well plates. The cells were treated with each inhibitor at the indicated concentrations for 1 h. Then, each of p43 or its deletion mutants was added at 100 nM to the cells and incubated for 20 h. The homotypic adhesion of THP-1 cells was observed by microscope at 100x magnification or quantified by counting the adhesive cells in the representative aliquots from each culture on a hematocytometer as a modified method of Takeda et al. [¹⁹ ]. Briefly, after the THP-1 cells were treated with none or p43, the THP-1 cells in aggregates coagulated with more than three cells were counted on the hematocytometer as the adhesive cells. We counted the adhesive cells in at least 600 cells for each execution. Degree of aggregation was calculated by the ratio of the number of the adhesive cells to the number of total cells.

For neutralization, the cells were pretreated with mouse anti-CD11a (MAB1386; Chemicon, El Segundo, CA), anti-CD11b (MAB1380; Chemicon), and anti-ICAM-1 (Chemicon) antibodies 1 h before p43 treatment. Quantification was performed as described above.

Assay of gene expression by cDNA array analysis
The Atlas Human cDNA Expression Array 1.2 (Clontech, Palo Alto, CA) was used for cDNA array analysis. Total and polyadenylated RNAs were prepared from the control or p43-treated THP-1 cells by the Atlas Pure Total RNA labeling system (Clontech) as recommended by the manufacturer. Polyadenylated RNA (1 µg) isolated from the control or p43-treated cells was converted to radioactive cDNA by reverse transcription (RT) in the presence of [-³²P]-dATP. The radioactively labeled cDNA was then denatured and hybridized to the cDNA expression arrays as recommended by the manufacturer. The radioactivity on the membranes was quantified by a phosphoimager. We calculated the change in gene expression after p43 treatment as the percentage of the untreated cells, using three of the internal controls recommended by the manufacturer for normalization to ensure the comparability of the control and p43-treated samples.

Quantitative RT-PCR analysis
RNA (2 µg) was converted to cDNA by RT using Moloney murine leukemia virus (M-MLV) RT (Gibco BRL) and the anchored oligo-dT primer set. The cDNA was then amplified by PCR using the ICAM-1 primers: sense, 5'-TCACATGACTAAGCCAAGAG-3'; antisense, 5'-CTGAGTGTCATTGTGAACAC-3'.

The reaction was run at 94°C (1 min), 58°C (40 s), and 72°C (50 s) for 35 cycles, which was within the linear reaction window. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in the same cDNA was also measured as control by RT-PCR using the GAPDH primers: sense, 5'-TCATTGACCTCAACTACATG-3'; antisense, 5'-CCAAAGTTGTCATGGATGAC-3'. After amplification, the PCR products were resolved by agarose-gel electrophoresis.

Fluorescein-activated cell sorter (FACS) analysis of ICAM-1 surface expression on THP-1 cells
THP-1 cells (2x10⁵/ml) grown in six-well plates were treated with none or 100 nM p43 for 18 h. Cells were then harvested, washed, and stained with 10 µg fluorescein isothiocyanate (FITC)-conjugated anti-CD54 antibody (Chemicon) for 3 h at 4°C. After washing, stained cells were analyzed by flow cytometry using Becton-Dickinson (San Jose, CA) FACS Caliber.

	RESULTS

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Monocyte cell adhesion is induced by p43
Homo- and heterotypic cell adhesion is not only involved in inflammation but also in morphogenesis, wound repair, tumor growth, and metastasis [¹⁷ , ^{20 21 22 23} ]. We tested whether p43 induces hetero- and homotypic adhesion of myelomonocytic THP-1 cells. p43 stimulated the homotypic adhesion of THP-1 cells (Fig. 1 ) as well as their heterotypic adhesion with HUVECs (human umbilical vein endothelial cells; unpublished results). Here, we have just focused on the homotypic adhesion of THP-1 cells for experimental convenience because the same adhesion molecule induced by p43 is expected to be involved in homo- and heterotypic cell adhesions [²⁴ , ²⁵ ]. The homotypic THP-1 cell adhesion was observed at 10–100 nM p43 (Fig. 1) . Although a relatively high amount of p43 was used to induce ICAM-1 and cell aggregation (Figs. 1 and 2), it appears to be a result of the low sensitivity of THP-1 cells to p43. p43 Induced the THP-1 cell adhesion with the maximal effect about 18 h after p43 treatment (Fig. 1) . The extended time course of p43-induced cell adhesion suggests that the de novo synthesis of (an) adhesion molecule(s) should be required.

View larger version (99K): [in this window] [in a new window]   Figure 1. Induction of homotypic adhesion of monocytic THP-1 cells by p43. THP-1 cells were untreated (Control) or treated with 100 nM p43. The cell adhesion was monitored microscopically and shown on the top panel. After quantification, the dose curve and the time course of p43-induced cell adhesion were plotted as a bar and line graph, respectively. For the dose curve, the cells were treated with p43 for 20 h. The bar and line graphs show the means ± SE obtained from four independent experiments.

View larger version (34K): [in this window] [in a new window]   Figure 2. ICAM-1 expression was up-regulated by the treatment of THP-1 with p43. (A) THP-1 cells were treated with 100 nM p43 for the indicated time points, and the expression of the eight different cell adhesion molecules was determined by the hybridization analysis of cDNA array. Expression of each gene was quantified by a phosphoimager and normalized based on three housekeeping genes (cytoplasmic ß-actin, 60S ribosomal protein L13A, and 40S ribosomal protein S9). The bar graph is representative of four independent experiments. (B) The expression of ICAM-1 mRNA was monitored by RT-PCR, after the THP-1 cells were treated with 100 nM p43 for indicated time points. GAPDH mRNA was also monitored as a control. ICAM-1 and GAPDH mRNAs were resolved by agarose gel electrophoresis. The gel picture is representative of three independent experiments. (C) The protein amounts of ICAM-1 were detected by Western blot analysis after THP-1 cells were treated with 100 nM p43 for indicated time points. Tubulin was also blotted for a control. The gel picture shown here was representative of three independent experiments. (D) ICAM-1 surface expression on THP-1 cells was measured by FACS analysis. After treatment with none or p43, cells were harvested, washed, and stained with 10 µg FITC-conjugated anti-ICAM-1 antibody for 3 h at 4°C. After washing, stained cells were analyzed by flow cytometry (Becton-Dickinson FACS Caliber). The mean fluorescence intensity (MFI) of p43-untreated cells with anti-p43 antibody to MFI of p43-treated cells with anti-p43 antibody is 1.5. The number of experiments with similar results = 3.

View larger version (51K): [in this window] [in a new window]   Figure 3. ICAM-1, LFA-1, and Mac-1 play a critical role in p43-induced cell adhesion. (A) Cells were preincubated with each of the indicated antibodies and then treated with 100 nM p43. The homotypic adhesion was detected under the microscope. (B) The homotypic adhesion was quantified as described in Materials and Methods. The bar graphs represent the means ± SE obtained in four independent experiments.

View larger version (19K): [in this window] [in a new window]   Figure 4. THP-1 cells were pretreated with none or 5 µg/ml cycloheximide 30 min before incubation with 100 nM p43. The cells were aggregated by treatment with p43 alone (•), but the cell adhesion was not seen in cells treated with cycloheximide alone () or p43 + pretreatment with cycloheximide ().

View larger version (33K): [in this window] [in a new window]   Figure 5. PI3-K, ERK, and p38 MAPK inhibitors blocked p43-induced THP-1 cell adhesion and expression of ICAM-1. (A) THP-1 cells were preincubated with none, WT (100 nM), LY (10 µM), PD (10 µM), or SB (10 µM) and then treated with 100 nM p43 for 20 h. Homotypic cell adhesion was monitored as in Figure 1 . (B) THP-1 cells were pretreated LY (10 µM), PD (10 µM), or SB (10 µM) and incubated for 2 h in the absence or presence of p43. ICAM-1 gene expression was quantified as described in Figure 2A . CD11a gene expression was seen as a control. (C) ICAM-1 expression in the THP-1 cells treated consecutively with none or each inhibitor (2 h), and p43 (20 h) was detected by Western blot analysis as in Figure 2C .

View larger version (42K): [in this window] [in a new window]   Figure 6. ERK activation is mediated by p43-induced PI3-K. (A) The THP-1 cells treated with 100 nM p43 were harvested, and the activity of PI3-K was determined as described in Experimental Procedures. PI3-K was precipitated with the antibody specific to PI3-K subunit, p85, and its phosphorylation was determined with antiphosphotyrosine antibody. (B) The THP-1 cells were preincubated with WT (100 nM) or LY (10 µM) for 1 h and incubated for 1 h in the absence or presence of p43. The proteins extracted from the treated cells were resolved by SDS-PAGE, and the activities of ERK and p38 MAPK were determined by phosphorylation of ERK and p38 MAPK, respectively. (C) Quantification of Western blot for phosphorylation of ERK has been performed by densitometry. The bar graph shows the mean ± SE (n=3). The solid and open bars stand for the activities of ERK in the presence and absence of p43, respectively.

Deletion mapping of p43
Because the full length of p43 had a stimulatory effect on cell adhesion, we investigated which region of p43 is responsible for cell adhesion. The full-length p43 and its deletion mutants were expressed as recombinant proteins and purified to homogeneity. After removing trace amount of the contaminating LPS, each of the purified proteins was used for the experiments. THP-1 cells were treated with each of the purified proteins, and cell aggregates were observed 20 h after the treatment. The active domain was determined by monitoring the degree of the induced homotypic cell aggregation. Many purified p43 fragments were able to induce the homotypic cell adhesion, and the C-terminal fragments of p43 composed of residues 218–312 and 257–312 were inactive (Fig. 7 ). It is interesting that the full length or the peptides spanning outside of the EMAP II domain (residues 147–312) showed higher cell adhesion activity.

View larger version (12K): [in this window] [in a new window]   Figure 7. Schematic diagram of p43 and its deletion mutants and their activities to induce the homotypic cell-cell adhesion. Each peptide was added at 100 nM. The bar graphs show the mean ± SE (n=3).

	DISCUSSION

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View larger version (12K): [in this window] [in a new window]   Figure 8. A proposed signaling pathways leading to p43-induced cell adhesion. ERK and p38 MAPK are activated by a PI3-K-dependent and -independent manner, respectively. The activation of these kinases up-regulates the expression of ICAM-1, which is directly involved in cell-cell adhesion.

The function of p43 is not clear as to whether p43 activates integrin ß₂ family members. Because p43 activates upstream signaling molecules, PI3-K and ERK, for integrin ß₂ family members [¹⁷ , ³⁹ ], p43 is possible to enhance the avidity and/or binding activity of integrin ß₂ family members. However, up-regulation of ICAM-1 induced by p43 is critical in THP-1 homotypic cell adhesion, because kinetics for cell adhesion is corresponding to the time course of ICAM-1 expression (Figs. 2 and 3) , and more importantly, p43-induced cell adhesion was completely prevented by a protein synthesis inhibitor (Fig. 4) . The results indicate that p43-induced cell adhesion requires up-regulation of ICAM-1 expression, but this work does not rule out a possible activity of p43 to alter the activity and/or the avidity of adhesion molecules.

We also investigated how p43 induces the expression of ICAM-1. Three MAPK family members and NF-B were shown previously to be activated by p43 [⁸ ]. These signaling molecules are involved in intercellular adhesion of various cell types. NF-B mediates cellular adhesion by the regulation of ICAM-1 expression in human fibroblasts and pancreatic acinar cells [¹³ , ¹⁴ ]. ERK and PI3-K have been shown to be upstream regulators for integrin ß₂-mediated cellular adhesion [¹⁷ , ³⁹ ]. Here, we dissected the p43-induced signaling pathway in a more systematic and detailed manner. PI3-K, ERK, and p38 MAPK have been found to regulate the homotypic THP-1 cell adhesion. These kinases are organized into PI3-K/ERK-dependent and p38 MAPK-dependent pathways (Fig. 8) . A bifurcating point of the two parallel signaling pathways lies upstream of PI3-K. NF-B remains to be studied as to whether it is involved in p43-dependent cell adhesion. p43-Dependent multiple signaling pathways determined here would give an important insight to understand the working mechanism of this novel cytokine. In conclusion, the results of this work identified that p43 stimulates different MAPKs via PI3-K-dependent and -independent ways, leading to cell-cell adhesion of monocytes (Fig. 8) , and implicates p43 for the potent role in inflammatory and atherosclerotic processes.

	ACKNOWLEDGEMENTS

 
This work was supported by a grant from the National Creative Research Initiatives of the Ministry of Science and Technology of Korea.

Received July 7, 2001; revised September 11, 2001; accepted October 5, 2001.

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TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

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