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(Journal of Leukocyte Biology. 2001;69:435-439.)
© 2001 by Society for Leukocyte Biology

Lymphocytes induce monocyte chemoattractant protein-1 production by renal cells after Fc{gamma} receptor cross-linking: role of IL-1ß

Brad H. Rovin, Ling Lu and Clay B. Marsh

Department of Internal Medicine and the Heart Lung Research Institute, The Ohio State University School of Medicine and Public Health

Correspondence: Brad H. Rovin, M.D., Nephrology Division, Ohio State University, N210 Means Hall, 1654 Upham Dr., Columbus, OH 43210. E-mail: rovin.1{at}osu.edu


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ABSTRACT
 
Leukocyte recruitment to the kidney in immune complex disease like systemic lupus erythematosus (SLE) is mediated in part by local expression of chemokines such as monocyte chemoattractant protein-1 (MCP-1). Recent studies from this laboratory demonstrated that cross-linking Fc{gamma}R on lymphocytes causes release of a soluble factor that induces monocyte chemokine production. To explain the induction of renal chemokine expression in immune complex disease, we postulated that this lymphocyte factor stimulates renal parenchymal cell MCP-1 expression. To test this hypothesis, human peripheral blood lymphocytes were incubated on immobilized IgG, a model for immune complex Fc{gamma}R cross-linking. Supernatants from these lymphocyte cultures significantly increased MCP-1 production by human mesangial, glomerular capillary endothelial, and proximal tubular epithelial cells. Mesangial cells incubated on immobilized IgG or with soluble, preformed immune complexes did not secrete MCP-1 above control levels. Lymphocyte supernatant-induced MCP-1 production appeared to be dependent on the presence of interleukin (IL)-1ß in the supernatant. Removing IL-1ß from the supernatants, antagonizing its activity, or preventing conversion to mature IL-1ß abrogated renal cell MCP-1 expression by the lymphocyte supernatants. These data demonstrate that in response to cross-linking Fc{gamma}R, lymphocytes induce renal cell MCP-1 expression by secreting IL-1ß. Renal chemokine expression in immune complex disease may thus be triggered as lymphocytes traffic through the kidney and encounter deposited immune complexes.

Key Words: chemokine • mesangial • immune complex


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INTRODUCTION
 
Leukocyte infiltration of the kidney during immune complex-mediated diseases like systemic lupus erythematosus (SLE) depends in part on the local expression of chemokines such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8). This is clearly illustrated in murine models of SLE, where genetic deletion or pharmacological inhibition of MCP-1 significantly attenuates renal inflammation and reduces the proteinuria indicative of glomerular injury [1 , 2 ]. In human SLE nephritis, a role for chemokines is implied by the observations that MCP-1 and IL-8 can be localized to the kidney by immunohistochemical staining and in situ hybridization [3 4 5 ], and that urinary excretion of these chemokines increases during active disease and declines with treatment or remission [4 5 6 7 ].

Activation of receptors for the Fc portion of IgG (Fc{gamma} receptors, Fc{gamma}R) by immune complexes is the likely trigger for chemokine expression in SLE and similar diseases. A central role for Fc{gamma}R is supported by two observations. In animal models of immune complex injury, tissue leukocyte infiltration is abrogated in the absence of functional Fc{gamma}R [8 9 10 ]. Furthermore, we have shown that cross-linking Fc{gamma}R on human peripheral blood mononuclear cells (PBMC) induces the production of biologically active IL-8 and MCP-1 [11 12 13 ]. These studies demonstrated that the main cellular source of chemokines in the PBMC preparations was the monocyte, but that cross-linking Fc{gamma}RIII receptors on lymphocytes significantly augmented monocyte chemokine production through the release of a soluble factor [12 13 14 ]. This effect was specific to Fc{gamma}RIII, not Fc{gamma}RI or Fc{gamma}RII [13 , 14 ]. Applying these data to immune complex diseases affecting the kidney, we envision that upon encountering immune complexes deposited within the kidney, circulating Fc{gamma}RIII-bearing lymphocytes are activated to produce a lymphokine(s) capable of inducing chemokine expression by renal parenchymal cells. Renal inflammation is then initiated as the chemokines recruit leukocytes to the kidney.

To examine the feasibility of this proposed mechanism, primary cultures of human renal parenchymal cells were treated with supernatants from lymphocytes cultured on immobilized human IgG, a stimulus for Fc receptor cross-linking [11 ]. Production of biologically active MCP-1 by these renal cells was measured. In addition, studies were conducted to identify the lymphokine responsible for inducing parenchymal chemokine expression.


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MATERIALS AND METHODS
 
Lymphocyte isolation and treatment
PBMC from heparinized venous blood of normal human volunteers were purified and enriched for lymphocytes as previously detailed [11 ]. Lymphocytes were resuspended in RPMI 1640 (BioWhittaker, Walkersville, MD) containing 5% fetal calf serum (FCS) and 10 µg/mL polymyxin B (Rohrer Pharmaceuticals, New York, NY), at a concentration of 5 x 106 lymphocytes/mL. Although all reagents used in these experiments contained less than 10 pg/mL of endotoxin, as assessed by the Limulus amebocyte lysate assay (Associates of Cape Cod, Woods Hole, MA), polymyxin B was added to cell culture media to ensure that the results were not influenced by residual endotoxin [15 ]. By FACS analysis, 98% of the cells were CD14-, and 14.7% of the cells were positive for Fc{gamma}RIII.

Purified lymphocytes were incubated for 18 h in 96-well plates (Immulon IV, Dynatech, Chantilly, VA) on which pooled human IgG (25 µg/well) had been immobilized or in media alone. IgG was immobilized on the tissue culture plates as previously described [12 ]. Cell-free supernatants were harvested and diluted fivefold, or as indicated, for use with the human renal parenchymal cells (see below). In some experiments Ac-Tyr-Val-Ala-Asp-chloromethylketone (YVAD-CMK, Calbiochem, Cambridge, MA), an IL-1-converting enzyme inhibitor was added to the lymphocytes cultured on immobilized IgG. In other experiments, IL-1ß was removed from the lymphocyte supernatants by three cycles of immunoprecipitation. Each cycle consisted of supernatant incubation for 1 h at 4°C with mouse anti-human IL-1ß (clone 8516.311, R & D Systems, Minneapolis, MN), followed by rat anti-mouse IgG1 coupled to Sepharose beads (Zymed, San Francisco, CA) for 1 h at 4°C, and centrifugation. Non-immune mouse monoclonal IgG1 was used as a control for these studies. This protocol was able to decrease mesangial MCP-1 production induced by human recombinant IL-1ß by 91%.

Human renal cell culture and treatment
Human renal mesangial cells, glomerular capillary endothelial cells (GCEC), and proximal tubular epithelial cells (PTEC) were cultured from kidneys not suitable for transplantation. Mesangial cells from at least three different donors were isolated and characterized as we have previously described [16 ], and used between passages 5 and 7. GCEC and PTEC were gifts of Dr. John Mahan and Dr. Marty Turman, Nephrology Division, Children’s Hospital (Columbus, OH). The purification and characterization of these cells has been detailed elsewhere [17 , 18 ].

Renal parenchymal cells were cultured in media alone, or with lymphocyte supernatants prepared as described above, for 18 h. In some experiments a combination of the IL-1 receptor antagonist (IL-1Ra, gift of Dr. Daniel Tracey, Upjohn Laboratories) and the soluble type II IL-1 receptor (sIL-1R) was added to the renal cells cultured with lymphocyte supernatants. This was done to prevent the interaction of IL-1ß with its signaling receptor (type I) on renal cells. In other experiments mesangial cells were incubated on immobilized IgG or with soluble immune complexes consisting of bovine IgG (BGG) and monkey anti-BGG. The preparation of these BGG:anti-BGG immune complexes has been described previously [19 ]. Cell-free supernatants were harvested for MCP-1 enzyme-linked immunosorbent assay (ELISA), and cells were used to prepare total RNA.

Measurement of renal parenchymal cell MCP-1 expression
Renal cell production of MCP-1 was determined using a modification [6 ] of the double-ligand ELISA originally developed by Evanoff et al. [20 ]. The capture antibody was a mouse monoclonal anti-human MCP-1 (R & D Systems) and the upper antibody was a rabbit polyclonal anti-human MCP-1 (PeproTech, Rocky Hill, NJ). A horseradish peroxidase-conjugated goat anti-rabbit antibody was used for detection. The standard curve was constructed with human recombinant MCP-1 (PeproTech). The ELISA was sensitive to 100 pg/mL.

MCP-1 mRNA was measured by Northern blotting of total renal cell RNA, as we have previously described [16 ]. The MCP-1 probe was a XhoI fragment from phJE34 (American Type Culture Collection, Rockville, MD). The blots were reprobed for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) with the use of a full-length human cDNA (Clontech, Palo Alto, CA), to normalize for variations in RNA loading.

Statistical analysis
Results are expressed as means ± SEM. Unpaired Student’s t tests were used to compare two conditions. When more than two conditions were compared, analysis of variance with Bonferroni’s post hoc testing was used.


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RESULTS
 
Supernatants from IgG-stimulated lymphocytes induce renal parenchymal cell expression of MCP-1
Supernatants from lymphocytes cultured on tissue culture plastic (control) or immobilized IgG were incubated with human mesangial cells, GCEC, or PTEC. As shown in Figure 1A , supernatants from the IgG-treated lymphocytes caused each renal cell type to secrete significantly more MCP-1 than supernatants from control lymphocytes. Treatment of mesangial cells with a series of lymphocyte supernatant dilutions showed an approximately linear relationship between MCP-1 production and supernatant concentration, with a plateau between 20 and 25% lymphocyte supernatant (Fig. 1B) . As expected, the increased MCP-1 production was accompanied by an increase in MCP-1 mRNA expression in response to supernatants from IgG-treated lymphocytes. This is illustrated for mesangial cells in Figure 2B .



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  		Figure 1. Renal parenchymal cells produce MCP-1 in response to supernatants from lymphocytes cultured on immobilized IgG. (A) Mesangial cells, GCEC, or PTEC were incubated overnight in media containing 20% lymphocyte supernatant. MCP-1 production was measured by ELISA, and normalized to the total amount of cell protein present. Supernatants were from lymphocytes grown on plastic (CONT) or on immobilized IgG (iIgG). Results were combined from individual experiments using lymphocytes from two to four donors, performed in triplicate. (B) MCP-1 production by mesangial cells was measured in response to increasing concentrations of lymphocyte supernatant. MCP-1 is expressed as a percent of the value obtained with a lymphocyte supernatant concentration of 20%, which was used for most of the experiments in this study. For the portion of the curve between 0 and 20% supernatant, the r2 value was 0.92. Results were combined from three different lymphocyte supernatants.



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  		Figure 2. Mesangial cell MCP-1 mRNA expression in response to lymphocyte supernatants. Mesangial cells were treated with IL-1ß (1.1 ng/mL), TNF-{alpha} (10 ng/mL), or supernatants from IgG-treated lymphocytes (LYG), in the presence or absence of the IL-1ß inhibitors (INH) IL-1Ra (10 ng/mL) and sIL-1R (10 ng/mL). After 18 h, total RNA was harvested and probed for MCP-1 mRNA. Blots were reprobed for GAPDH to account for differences in RNA loading. (A) The IL-1ß inhibitors specifically antagonize the effects of IL-1ß. (B) The IL-1ß inhibitors significantly attenuate the induction of MCP-1 mRNA by lymphocyte supernatants. Representative of two independent experiments.

Incubation of mesangial cells on immobilized IgG did not stimulate MCP-1 production (Table 1 ). In parallel experiments, the mesangial cells did produce MCP-1 in response to IL-1ß (Table 1) . In another experiment, mesangial cells were incubated with pre-formed, soluble BGG:anti-BGG immune complexes. As shown in Table 1 , MCP-1 production was no different than cells cultured in media, media containing only antigen (BGG), or only antibody (anti-BGG). Consistent with this observation, soluble immune complexes did not induce mesangial MCP-1 mRNA expression (data not shown). The BGG:anti-BGG immune complexes did, however, cause a dose-dependent increase in PBMC MCP-1 production, validating their usefulness as a Fc{gamma}R stimulus (Table 1) . No surface expression of Fc{gamma}RIII on the mesangial cells was found by FACS analysis using the anti-Fc{gamma}RIII antibody Gran-1 (data not shown).


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  		Table 1. Effect of Immobilized IgG (iIgG) and BGG:Anti-BGG Immune Complexes (IC) on Mesangial MCP-1 Production

IL-1ß inhibitors decrease the activity of supernatants from IgG-stimulated lymphocytes
Consistent with previous observations from this laboratory [14 ], purified lymphocytes cultured on immobilized IgG released a significant amount of IL-1ß (2.2 ± 0.8 compared to 0.03 ± 0.05 ng/mL from lymphocytes incubated on plastic, P < 0.04, n = 4). This appears to be due specifically to Fc{gamma}RIII-bearing lymphocytes, which have been shown to produce fourfold more IL-1ß (2.6 ± ng/mL vs. 0.6 ± 0.6 ng/mL) than Fc{gamma}RIII-negative lymphocytes in response to immobilized IgG [14 ]. Because IL-1ß is a potent stimulus for MCP-1 production by renal parenchymal cells [16 , 21 ], experiments were done to determine whether IL-1ß is responsible for the chemokine-inducing activity of supernatants from IgG-stimulated lymphocytes. In these studies, three approaches were used to inhibit IL-1ß activity. First, the IL-1-converting enzyme inhibitor YVAD-CMK was added to lymphocytes cultured on immobilized IgG to prevent conversion of precursor IL-1ß to the active cytokine. YVAD-CMK caused a dose-dependent inhibition of the MCP-1-inducing activity of supernatants from IgG-treated lymphocytes (Fig. 3A ). In four experiments YVAD-CMK (100 µg/mL) reduced mesangial MCP-1 production in response to lymphocyte supernatants by 84 ± 2.7% (P< 0.001). In another series of experiments, IgG-treated lymphocyte supernatants were incubated with a monoclonal IL-1 neutralizing antibody (2 µg/mL) followed by anti-mouse IgG coupled to Sepharose beads to remove IL-1ß. Mesangial cells conditioned with these supernatants produced approximately 60% less MCP-1 compared to untreated lymphocyte supernatants, or supernatants treated with a non-immune isotype control antibody (Fig. 3B) . Similar studies using a rabbit polyclonal anti-IL-1ß antibody for immunoprecipitation showed a 64 ± 4.2% reduction in MCP-1 production, with inhibition ranging from 58.5 to 76.3% (n = 4). Finally, a combination of the sIL-1R type II (20 ng/mL) and IL-1Ra (250 ng/mL) added to human mesangial cells incubated with supernatants from IgG-treated lymphocytes resulted in a 78% reduction in MCP-1 expression, compared to mesangial cells incubated with lymphocyte supernatants alone (Fig. 3C) . The combination of sIL-1R and IL-1Ra also attenuated the up-regulation of MCP-1 mRNA by supernatants from IgG-treated lymphocytes (Fig. 2B) . IL-1Ra and sIL-1R blocked renal cell MCP-1 production in response to IL-1ß, but had no effect on tumor necrosis factor {alpha} (TNF-{alpha})-induced MCP-1 expression, (Fig. 2A) . These IL-1 inhibitors had a similar effect on MCP-1 production by GCEC and PTEC (data not shown).



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  		Figure 3. Inhibition of lymphocyte supernatant IL-1ß activity attenuates supernatant-induced MCP-1 production by mesangial cells. (A) Lymphocytes cultured on immobilized IgG were incubated with the indicated concentrations of the IL-1-converting enzyme inhibitor YVAD-CMK. Supernatants from these cells were incubated with human mesangial cells, and MCP-1 production measured by specific ELISA. The results shown are representative of two independent experiments. (B) Supernatants from lymphocytes cultured on immobilized IgG were untreated (CONT), treated with non-immune mouse IgG1 + anti-mouse IgG1-Sepharose (non-immune), or mouse anti-human IL-1ß + anti-mouse IgG1-Sepharose (Anti-IL-1). The Sepharose-bound immune complexes were removed by centrifugation before treating mesangial cells with the supernatants. MCP-1 production was measured by specific ELISA (*P < 0.001 vs. CONT and Non-immune, n = 4 lymphocyte donors). In this experiment mesangial cells produced 29.8 ± 2.1 ng MCP-1/mg cell protein in the absence of lymphocyte supernatants. (C) Mesangial cells were treated with supernatants from lymphocytes incubated on plastic (CONT), or immobilized IgG (iIgG) in the presence or absence of sIL-1R type II (20 ng/mL) plus IL-1Ra (250 ng/mL; INH). MCP-1 was measured by specific ELISA. The results represent the mean of duplicate experiments, with the error bars representing the range for the duplicates.


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DISCUSSION
 
This investigation demonstrates that lymphocytes incubated on immobilized IgG produce a soluble factor(s) that dose-dependently induces MCP-1 production by human renal parenchymal cells. This lymphocyte factor up-regulates both MCP-1 mRNA expression and protein synthesis. Renal parenchymal cell MCP-1 production in response to Fc{gamma}R agonists appears to require a paracrine factor contributed by leukocytes, because direct culture of mesangial cells on immobilized IgG, or incubation of mesangial cells with soluble immune complexes, did not elicit MCP-1 expression. The major contribution to the chemokine-inducing activity of these supernatants appears to be from IL-1ß produced by lymphocytes in response to Fc{gamma}R cross-linking. The dose-response relationship between lymphocyte supernatant concentration and MCP-1 production does not suggest the presence of an endogenous MCP-1 inhibitor in these supernatants. Blocking IL-1-converting enzyme, antagonism of the IL-1 type I receptor, or immunoadsorption of IL-1ß from the lymphocyte supernatants each caused a significant reduction (60–84%) in the capacity of these supernatants to induce MCP-1. Immunoprecipitation of IL-1ß was somewhat less effective than treatment with YVAD or the IL-1 receptor blockers in attenuating the bioactivity of lymphocyte supernatants. This raises the possibility that additional factors in the lymphocyte supernatants can induce MCP-1; however, the convincing inhibition with YVAD and the IL-1 receptor antagonists suggests that these additional factors may be IL-1-related.

These data extend our previous observation that cross-linking Fc{gamma}RIII on lymphocytes induces IL-1ß that can then mediate fibroblast or mesangial cell IL-8 production [14 ]. Taken together, these studies provide evidence supporting a paradigm that renal chemokine expression in immune complex disease is regulated by the interaction between immune complexes and Fc{gamma}RIII. In this paradigm, circulating Fc{gamma}RIII-bearing lymphocytes play a central role, transducing the signal from immune complexes into a cytokine (IL-1ß) capable of stimulating local chemokine production. Once produced, MCP-1 could further enhance this pathway by recruiting additional lymphocytes to the kidney [21 ] that would be available to interact with immune complexes. Although we favor tissue parenchymal cells as the primary source of chemokines, it is also possible that circulating or resident monocytes/macrophages contribute to local chemokine production [13 ], and amplify the inflammatory response. Because this model requires the presence of circulating lymphocytes, severe inflammation should be observed mainly when immune complexes deposit in areas accessible to leukocyte traffic. This appears to be consistent with the pathology of SLE nephritis, a model of immune complex disease. In SLE, glomerular subendothelial or mesangial immune complexes tend to be associated with a more inflammatory lesion than immune complexes that are found mainly in the subepithelial space [22 ].

Using rodent mesangial cells, it has been shown that incubation with heat-aggregated IgG, a Fc{gamma}R stimulus, up-regulates MCP-1 production [23 , 24 ]. It may thus be argued that immune complexes can activate renal chemokine expression directly, by cross-linking Fc{gamma}R on mesangial cells, eliminating the need for lymphocyte trafficking through the kidney to engage deposited immune complexes as the initial step in chemokine production. Unlike rodent mesangial cells, which constitutively express (at least) Fc{gamma}RII [25 ], adult human mesangial cells must be activated to express Fc{gamma}R [26 , 27 ]. This is consistent with our observation that resting human mesangial cells did not respond to two different Fc{gamma}R stimuli, immobilized IgG, or soluble immune complexes. Human mesangial Fc{gamma}RI and Fc{gamma}RIII expression has been induced using interferon-{gamma} plus endotoxin [26 , 27 ]. Furthermore, cross-linking Fc{gamma}RI on interferon-activated human mesangial cells was shown to elicit MCP-1 and IL-8 expression [27 ]. It is interesting that in our study incubation of lymphocytes on immobilized IgG caused secretion of a significant amount of interferon-{gamma} (1.54 ± 0.2 ng/mL interferon-{gamma}, compared to no detectable interferon-{gamma} from lymphocytes grown on plastic, n = 3 [Rovin and Marsh, unpublished observations]). Thus, interferon-{gamma} produced in response to cross-linking Fc{gamma}RIII on lymphocytes could result in induction of Fc{gamma}R expression on renal cells, allowing these cells to respond directly to immune complexes. This may serve to further amplify the inflammatory response.

In summary, the present observations support a central role for Fc{gamma}RIII-bearing lymphocytes in orchestrating the inflammatory mediators responsible for recruiting leukocytes to the kidney in immune complex disease. The exact subpopulation of lymphocytes involved in these events remains to be identified, however, NK cells and {gamma}{delta} T cells both express Fc{gamma}RIII [28 , 29 ], and are thus likely candidates. Identifying a lymphocyte population responsible for inducing chemokine expression and regulating leukocyte recruitment to the kidney should permit the development of selective cytotoxic therapy to control renal inflammation in diseases like SLE.


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ACKNOWLEDGEMENTS
 
This work was supported by National Institutes of Health Grants DK46055, HL63800, and RR00034, the S. L. E. Foundation, Inc., and the American Lung Association. C. B. M. is a recipient of the Johnie Murphy Career Investigator Award.

Received June 1, 2000; revised October 26, 2000; accepted October 27, 2000.


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