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Stem Cells, Vol. 14, No. 2, 225-231, March 1996
© 1996 AlphaMed Press

ORIGINAL PAPER

Endogenously Produced Interleukin 6 is an Accessory Cytokine for Dendritic Cell Hematopoiesis

Frances Santiago-Schwarz, John Tucci, Steven E. Carsons

Division of Rheumatology, Allergy & Immunology, Winthrop University Hospital, Mineola, New York, USA; Department of Medicine, State University of New York at Stony Brook, New York, USA

Key Words. Dendritic cells • Cord blood • Interleukin 6 • Accessory cells • Hematopoiesis

Dr. Frances Santiago-Schwarz, Division of Rheumatology, Winthrop University Hospital, 222 Station Plaza North, Suite 430, Mineola, NY 11501, USA.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The aim of this study was to investigate the role of interleukin 6 (IL-6) in normal dendritic cell (DC) hematopoiesis. We used an enzyme-linked immunosorbent assay to quantitate IL-6 levels in CD34+ progenitor cell cultures favoring monocyte (mono) development versus those supporting mono-DC growth, and studied the neutralizing effects of {alpha}IL-6 antibody on DC hematopoiesis. IL-6 levels in mono cultures (GM-CSF alone) were detected by day 4 and remained constant (~100 pg/ml) for 18 days. In mono-DC cultures, higher IL-6 levels correlated with DC content and development. Short-term mono-DC cultures initiated with GM-CSF + tumor necrosis factor (TNF) + stem cell factor (SCF) exhibited increases in IL-6 levels until day 11 (peak DC growth). By day 18, the levels had declined and cells expressing typical DC features were no longer present. Long-term mono-DC cultures sustained with GM-CSF + TNF + SCF contained the highest IL-6 levels (671 pg/ml) on day 11. In these cultures, DCs and higher IL-6 levels persisted beyond 18 days. Anti-IL-6 profoundly inhibited cell proliferation associated with DC hematopoiesis when added on days 0, 2 and 5 to GM-CSF + TNF + SCF cultures, indicating that various stages of mono-DC development rely on IL-6. There was no reduction in the T cell response when {alpha}IL-6 was added to mixed leukocyte reaction cultures containing mature DCs as stimulators. Thus, {alpha}IL-6 appears to downregulate developmental processes associated with optimal mono-DC growth, but not the effector functions of mature DCs.

These studies substantiate the importance of IL-6 as a secondary cytokine during DC development and provide insight into another control point in the DC pathway.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Human dendritic cells (DCs) and monocytes (monos) develop simultaneously from a common progenitor when CD34+ cells from cord blood or bone marrow are treated with tumor necrosis factor (TNF) and GM-CSF [1-4]. TNF is the first signal required in this synergistic interaction and promotes high levels of GM-CSF receptors (Rs) and the inhibition of granulocyte differentiation [5]. Anti-GM-CSF severely inhibits development of all myeloid progeny in TNF + GM-CSF cultures, including monos, DCs and granulocytes. Anti-TNF selectively inhibits mono-DC development, while sparing granulocytic growth [5]. When combined with GM-CSF + TNF, stem cell factor (SCF) enhances the DC pathway without altering the developmental commitment instituted by GM-CSF and TNF [4-8]. It augments self-renewal events of mono-DC progenitors, as assessed by increases in colony size and number, and replating capacity [4, 6]. SCF also facilitates DC survival in long-term mono-DC cultures by suppressing DC apoptosis [9].

Interleukin 6 (IL-6) is an important secondary cytokine in GM-CSF-induced monocytopoiesis and a survival factor for colony-forming unit-granulocyte-macrophage (CFU-GM) [10, 11]. It is also produced as a secondary cytokine in response to TNF, when acute myeloid leukemia cells are treated with IL-3 + TNF [12]. Moreover, the terminal development of DCs from a myelodendritic cell leukemia (ORL47) is not induced by GM-CSF + TNF or GM-CSF + TNF + SCF, but is strictly dependent on the exogenous addition of IL-6 [13]. We therefore speculated that endogenous IL-6 production might be important for the development of monos-DCs from normal CD34+ progenitors. In this study, we investigate the secondary production of IL-6 in mono-DC cultures and study the effects of {alpha}IL-6 antibodies on the mono-DC pathway. Our results support that IL-6 is an accessory cytokine which promotes mono-DC hematopoiesis from normal CD34+ progenitors.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Enrichment of Neonatal Cord Blood-Derived Progenitor Cells
Cord blood was collected from healthy full-term infants into sterile heparinized containers during repeat caesarean sections, according to institutional guidelines. Mononuclear cells were prepared by density centrifugation on Lymphoprep gradients (endotoxin poor, Nyegaard, Norway) and placed on nylon wool columns for the isolation of nonadherent cells, as previously described [1, 4, 5]. Separation of CD34+ progenitor cells from the nonadherent population employed positive immunoselection using immunomagnetic beads (Dynabeads, Dynal Inc.; Oslo, Norway) as described elsewhere [1, 4, 5].

Liquid Cultures
CD34+ cells were adjusted to 0.4 x 105 cells/ml in RPMI 1640 medium (GIBCO; Grand Island, NY) containing 2 mM L-glutamine, 10 mM HEPES, 50 IU/ml penicillin, 50 µg/ml streptomycin, 5% pooled normal human serum (NHS/RPMI) and incubated in Teflon vials (Scientific Specialties Service; Randalstown, MD) at 37°C in a 5% CO2 humidified incubator. Monos and DCs were generated using previously established strategies. For induction of the mono-DC pathway, cultures were supplemented with GM-CSF + TNF (GT) and GM-CSF + TNF + SCF (GTS) at the onset of the culture period [1, 4, 5]. DCs generated under these conditions were: DR+, CD14–, nonphagocytic, negative for nonspecific esterase (NSE) activity and potent stimulators of a mixed leukocyte reaction (MLR), as previously defined [14-17]. The cells exhibited classical DC features upon transmission electron microscopic examination. Birbeck granules were rare and <=10% of the cells expressed CD1a antigens on day 10. Long-term mono-DC cultures were maintained by supplementing the GM-CSF + TNF + SCF cultures with the same cytokines every 48 h (GTS FED), as previously described [4, 6]. Cultures favoring mono development were instituted with GM-CSF alone [1]. Human recombinant (r)SCF (Genzyme; Boston, MA) was employed at 50 ng/ml, human rTNF-{alpha} (Knoll Pharmaceuticals; Whippany, NJ) at 500 U/ml, human rGM-CSF (Genzyme) at 100 U/ml. The optimal concentration for each factor was calculated after dose analysis, as previously described [1, 4, 5]. Rabbit (rb) polyclonal (IgG and IgM) {alpha} human IL-6 antibody (Ab) (Genzyme) was tested at 10 and 50 µg/ml where indicated. Normal rb serum (1:10 dilution) was used as a negative control for rb {alpha}IL-6. For each experiment, cultures containing NHS/RPMI without cytokines were compared to cultures supplemented with the various cytokine combinations. For in situ analyses and examination under phase microscopy, cultures were also established in either 24-well plates or Lab-Tek chamber slides (Nunc; Naperville, IL). As previously demonstrated by us and others, these conditions do not support the development of lymphocytes [1, 3, 4]. Because endotoxin (LPS) can induce the secondary production of IL-6 [18, 19], all cultures were maintained under endotoxin poor conditions, as previously described [20].

IL-6 Production
Cell-free supernatants were collected on days 4, 7, 11 and 18 from the various cultures and screened for IL-6 levels using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Genzyme, Predicta IL-6), exactly as recommended by the manufacturer. The sensitivity range of this assay is >=18 pg/ml.

Proliferation
Proliferative events were measured on various days by the uptake of [3H] thymidine and by manual hemacytometer-assisted cell counts (Improved Neubauer). For thymidine uptake, 0.5 µCi of [3H] thymidine (specific activity, 25 Ci/mmol, Amersham; Arlington, IL) was added to 100 µl aliquots taken from Teflon cultures and placed in 96-well microtiter plates. After 5 h of incubation, cells were harvested using an automated sample harvester and counted in a liquid scintillation counter. Results are expressed as the mean of triplicate samples and the SE was <=20% in all experiments.

Allogeneic MLR
Cells grown under various culture conditions were removed from Teflon cultures after 11 days, centrifuged twice in RPMI, adjusted to equal concentrations in 5% NHS/RPMI and irradiated with a 60Co source (for a total of 2000 rads). Varying numbers of these stimulator cells were then added to 96-well microtiter plates containing 5 x 104 responder cells/well (nylon wool enriched T cell populations obtained from normal peripheral blood). A proliferative response was measured after seven days of incubation by adding 0.5 µCi of [3H] thymidine to each well and harvesting the cells as described above. Thymidine uptake in irradiated stimulator cells and responder cells cultured alone as controls was <200 cpm.

Cytochemistry
Cells cultured in suspension (Teflon) were prepared for Wright stain (Hemacolor) and NSE analysis by depositing them onto slides by means of cytocentrifugation (Shandon; Pittsburgh, PA). Cells in chamber slides were stained in situ. No fewer than 500 cells were analyzed.

Statistics
Where indicated, Student's t-test was used to analyze data using a Crunch Interactive Statistical Package.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
IL-6 Levels During Development
Temporal analysis revealed the pattern of endogenous IL-6 production during mono/DC hematopoiesis. Figure 1Go illustrates IL-6 measurements in cultures supporting mono-DC hematopoiesis (GT, GTS, GTS FED) and those favoring mono (GM-CSF) development during 18 days of culture. With GM-CSF treatment, IL-6 was detected by day 4. The levels remained constant (<=100 pg/ml) throughout the culture period. In comparison, in cultures promoting DC growth, the pattern of IL-6 production was linked with the development of DCs, as previously detailed [1, 4, 5]. In GTS cultures, IL-6 levels increased until ~ day 11 (peak DC development) and declined by day 18, when typical DC features were no longer present. On day 11, IL-6 levels in GTS cultures had more than doubled compared to GM-CSF cultures (213 ± 15 versus 83 ± 8, pg/ml, respectively, p < 0.02). For GTS FED versus GM-CSF on day 11, IL-6 levels increased eight-fold (671 ± 157 versus 83 ± 8, pg/ml, respectively, p < 0.03). Compared to GTS, GTS FED cultures contained three times as much IL-6 (p = 0.05). Day 11 supernatants from cells cultured in NHS/RPMI alone contained 32 ± 5 pg/ml of IL-6. GM-CSF + SCF treatment did not produce increases in IL-6 compared to GM-CSF treatment (data not shown). Only GTS FED cultures, which exhibited prolonged DC growth, contained high levels of IL-6 on day 18. The differences in IL-6 levels between GTS and GTS FED cultures on day 18 were significant (55 ± 12 versus 380 ± 175, pg/ml, respectively, p = 0.046).



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  		Fig. 1. Pattern of endogenous IL-6 production during mono/DC development. Cell-free supernatants were harvested and subject to an ELISA measuring IL-6, as outlined in Materials and Methods. Mono development: = GM-CSF. Mono-DC development: {blacktriangledown} = GTS FED, {blacktriangleup} = GTS, {blacksquare} = GT. For each time point, results represent the mean of two to five experiments.

 
IL-6 Levels are Positively Associated with DC Content
In Figure 2Go, we depict IL-6 levels in relation to the absolute number of DCs in the various cultures during peak DC growth (day 11). In cultures containing combinations of GM-CSF, TNF and SCF, DCs comprise 40%-60% of the progeny [1, 4]. Most of the remaining cells are mono-m{Phi}s which have developed simultaneously with the DCs [1-6]. With GM-CSF treatment, 5%-10% of the progeny are DCs, while the remaining cells are monos and granulocytes [1, 4]. GM-CSF cultures containing ~0.25 x 105 DCs/ml contained the lowest levels (~83 pg/ml) of IL-6. Increasing levels of IL-6 (150, 213 and 671 pg/ml) were noted in GT, GTS and GTS FED cultures, which contained an average of 3.4 x 105, 4.7 x 105 and 7.2 x 105 DCs/ml, respectively.



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  		Fig. 2. Correlation of IL-6 levels with DC content on day 11. The absolute number of DCs per ml represents: Total number of cells per ml x % DCs ÷ 100. The % of DCs in G (GM-CSF) = 10%, in GT, GTS and GTS FED the % = 60%. For all conditions, mono-macrophages comprised the bulk of the remaining cell population. For DC content, n = 5 for G, 6 for GT, 14 for GTS and 3 for GTS FED. The differences in DC content between groups were significant (p <= 0.035).

 
Effects of {alpha}IL-6 Polyclonal Ab
Figure 3AGo illustrates the effects of {alpha}IL-6 Ab treatment on days 0, 2 and 5 in GTS cultures, as measured by thymidine uptake on day 8. Addition of {alpha}IL-6 on days 0 and 2 yielded 50%-60% decreases in proliferation versus untreated GTS cultures (p = 0.0003). When added on day 5, {alpha}IL-6 decreased proliferation by ~36% (p < 0.04). Nonimmune rb serum did not inhibit the GTS response on any day. Determination of hemacytometer-assisted cell counts revealed similar neutralizing effects of {alpha}IL-6, as shown in Figure 3BGo. On all days, the addition of {alpha}IL-6 to GTS cultures induced significant decreases (p <= 0.02) in the total number of cells/ml compared to the untreated GTS cultures.



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  		Fig. 3. The effect of rb polyclonal {alpha}IL-6 Ab (10 µg/ml) added to GTS cultures on either day 0, 2 or 5 on proliferation. A) Peak proliferative events, as measured by thymidine uptake on day 8. For days 0 and 2 versus untreated GTS cultures, p = 0.0003, n = 3-7. For day 5 versus untreated GTS cultures, p < 0.04, n = 4-7. Results represent the mean ± the SE. Nonimmune rb serum did not inhibit the GTS response. B) The total number of cells in mature mono-DC cultures, as determined by hemacytometer-assisted cell counts on day 11. Open bars = {alpha}IL-6, black bars = parallel GTS cultures. For day 0, p = 0.006 (n = 7), for day 2, p = 0.02 (n = 3), for day 5, p = 0.008 (n = 3).

 
While {alpha}IL-6 treatment reduced cell proliferation and number in GTS cultures, the proportion of surviving monos to DCs in these cultures remained unaffected (Fig. 4Go). Anti-IL-6 treatment did not alter the distribution of granulocytes (<=10%) or the NSE or phagocytic activity of the surviving progeny (data not shown). Cells obtained from GTS cultures treated with {alpha}IL-6 Ab on day 0 exhibited similar MLR stimulatory capacity to that of cells obtained from untreated GTS cultures (Fig. 5Go). Therefore, {alpha}IL-6 treatment during mono-DC hematopoiesis did not alter the MLR capacity of DCs. The addition of {alpha}IL-6 directly to MLR assays containing untreated GTS stimulators did not decrease the proliferative response (data not shown), indicating that the functional capacity of mature mono/DCs is also not affected by {alpha}IL-6. The latter results are consistent with those of Leenaerts et al., who demonstrated that {alpha}IL-6 did not inhibit the MLR stimulatory capacity of peripheral blood mononuclear cells [18].



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  		Fig. 4. Phase photomicrographs of GTS cultures treated with {alpha}IL-6 on day 0, taken on day 7. Although there were large decreases in cell density with {alpha}IL-6, the morphological features of the surviving cells appeared unaffected. Cells exhibiting monocyte and DC features were present under both conditions. Original magnification = 40 x.

 


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  		Fig. 5. The MLR potential of cells developing in the presence of {alpha}IL-6. The slight decrease in MLR activity in day 0-treated GTS cultures was not significant (p > 0.05). Results represent the mean ± SE of triplicate samples, at stimulator:responder ratios of .025:1. One of two representative experiments is shown.

 
Our results suggest a complex role for IL-6 in the development of DCs. Anti-IL-6 neutralized developmental processes associated with optimal mono-DC growth, but not the effector functions of mature DCs. Since {alpha}IL-6 did not alter the proportion of surviving monos to DCs, it appears to affect a common mono-DC progenitor. In support of this observation, Kerst et al. described that IL-6 is a survival factor for the colony-forming unit-granulocyte-macrophage (CFU-GM), which precedes the mono-DC CFU in development [11]. Since SCF induces progenitor cell renewal, it is possible that common mono-DC progenitors are still present on days 2 and 5 in our GTS cultures. If so, they would be subject to the negative effects of {alpha}IL-6. We further observed that rIL-6 added to GTS cultures at the onset did not produce a significant increase in the number of mono-DCs generated (n = 3, p > 0.05), suggesting that some differentiation events must occur within the CD34+ progenitor cell compartment before the cells become responsive to IL-6 (data not shown). Recent studies also show that committed mono-DC precursors are present by day 5 in GTS cultures derived from CD34+ progenitors [21] and that DC maturation from peripheral blood precursors (contained in fractions enriched for monos) is dependent on the endogenous production of IL-6 [22]. Thus, the possibility that IL-6 also facilitates later phases of mono-DC development cannot be discounted.

Jansen et al. established an important role for IL-6 in monocytopoiesis by demonstrating that the addition of {alpha}IL-6 to human bone marrow progenitor cultures on day 0 inhibits the development of GM-CSF-induced monocytic colonies in semisolid cultures by about 50% [10]. The similar requirement of DC development on IL-6 provides another example of the close ontogenic relationship between monos and DCs. As suggested by Jansen et al., for GM-CSF-driven monocytopoiesis [10], IL-6 may be produced by progenitor cells and/or their offspring during mono-DC development with GM-CSF, TNF and SCF. Since monos clearly produce IL-6 during monocytopoiesis [10, 11], it is likely that monos are primary producers of IL-6 during mono-DC hematopoiesis. Compared to monos, the cytokine profile of DCs is not well-defined [15]. It has been reported that murine cultures enriched in Langerhan's cells (an immature DC element of the skin) produce IL-6, but the possible contribution of contaminating keratinocytes in these cultures was not established [23]. Our preliminary in situ analysis with polyclonal {alpha}IL-6 yielded cytoplasmic staining in adherent monos, but not in adherent DCs, supporting the notion that monos are the primary producers of IL-6 in our system.

IL-6 has been shown to induce the expression of adhesion molecules on a variety of cell types [24, 25]. In the myeloid lineage, upregulation of adhesion molecules by IL-6 is most effective when combined with CSF factors inducing myelopoiesis, such as GM-CSF [24]. Since several classes of adhesion molecules are elevated on DCs and these are critical for DC functions [15, 16], we speculate that some IL-6 functions on the DC pathway reflect induction of adhesion molecules on the DC surface, including those involved in DC migration and homing.

The effects of {alpha}IL-6 are in marked contrast to the inhibitory effects of {alpha}TNF Ab, which selectively downregulates mono-DC hematopoiesis while sparing the development of granulocytes [5]. Because of the important role of granulocytes in innate immunity, {alpha}TNF may be more useful than {alpha}IL-6 in developing therapeutic strategies designed to downregulate the DC pathway in autoimmune diseases characterized by an excess of DCs, such as rheumatoid arthritis [26, 27]. In other pathological situations characterized by deficiencies in DC development such as the ORL47 myelodendritic leukemia [13], it may be useful to promote the terminal maturation of DCs with exogenous IL-6 + GM-CSF + TNF + SCF. This type of strategy would not only serve to control leukemic cell growth, but also to increase the level of immunocompetence in these patients.


   Acknowledgments
 
The authors gratefully acknowledge the cooperation of the nursing staff in Labor and Delivery, Department of Obstetrics and Gynecology at Winthrop University Hospital, in the collection of cord blood. We wish to thank in particular Ms. Joanne Pastore and Ms. Rhona Schlau. We are also grateful to Mr. Bob Eggers and Mr. Jay Podbielak for assistance with the irradiation protocol and to Dr. Donald Coppock for helpful discussions.


   Footnotes
 
Provisionally accepted September 28, 1995.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Santiago-Schwarz F, Belilos E, Diamond B et al. TNF in combination with GM-CSF enhances the differentiation of neonatal cord blood stem cells into dendritic cells and macrophages. J Leukoc Biol 1992;52:274–281.[Abstract]

  2. Reid CDL, Stackpoole A, Meager A et al. Interactions of tumor necrosis factor with granuloctye-macrophage colony-stimulating factor and other cytokines in the regulation of dendritic cell growth in vitro from early bipotent CD34+ progenitors in human bone marrow. J Immunol 1992;149:2681–2688.[Abstract]

  3. Caux C, Dezutter-Dambuyant C, Schmitt D et al. GM-CSF and TNF-{alpha} cooperate in the generation of dendritic Langerhans cells. Nature 1992;360:258–261.[Medline]

  4. Santiago-Schwarz F, Rappa D, Laky K et al. Stem cell factor augments tumor necrosis factor-granulocyte-macrophage colony-stimulating factor-mediated dendritic cell hematopoiesis. STEM CELLS 1995;13:186–197.[Abstract]

  5. Santiago-Schwarz F, Divaris N, Kay C et al. Mechanisms of TNF/GM-CSF induced dendritic cell development. Blood 1993;82:3019–3028.[Abstract/Free Full Text]

  6. Santiago-Schwarz F, Laky K, Carsons SE. Stem cell factor enhances dendritic cell development. In: Banchereau J, Schmitt D, eds. Dendritic Cells in Fundamental and Clinical Immunology. New York: Plenum Press, 1995:7-11.

  7. Saraya K, Reid CDL. Synergistic interaction between c-Kit ligand (SCF), GM-CSF and TNF promotes optimal dendritic Langerhans cell proliferation from primitive progenitors in human bone marrow. In: Banchereau J, Schmitt D, eds. Dendritic Cells in Fundamental and Clinical Immunology. New York: Plenum Press, 1995:13-16.

  8. Young J, Szabolcs P, Feller E et al. Large numbers of immunostimulatory DC can be generated from human CD34+ bone marrow progenitors under the aegis of c-Kit ligand, GM-CSF, and TNF{alpha}. In: Banchereau J, Schmitt D, eds. Dendritic Cells in Fundamental and Clinical Immunology. New York: Plenum Press, 1995:17-20.

  9. Santiago-Schwarz F, Borrera M, Tucci J et al. The role of apoptosis in regulating dendritic cell development and survival. Arthritis Rheum 1995;38:R35.

  10. Jansen JH, Kluin-Nelemans JC, Van Damme J et al. Interleukin 6 is a permissive factor for monocytic colony formation by human hematopoietic progenitor cells. J Exp Med 1992;175:1151–1154.[Abstract/Free Full Text]

  11. Kerst JM, Slaper-Cortenbach ICM, Ellen van der Schoot C et al. Interleukin-6 is a survival factor for committed myeloid progenitor cells. Exp Hematol 1993;21:1550–1557.[Medline]

  12. Brach M, Gruss HJ, Asano Y et al. Synergy of interleukin 3 and tumor necrosis factor {alpha} in stimulating clonal growth of acute myelogenous leukemia blasts is the result of induction of secondary hematopoietic cytokines by tumor necrosis factor {alpha}. Cancer Res 1992;52:2197–2201.[Abstract/Free Full Text]

  13. Santiago-Schwarz F, Coppock DL, Hindenburg AA et al. Identification of a malignant counterpart of the monocyte-dendritic cell progenitor in an acute myeloid leukemia. Blood 1994;84:3054–3062.[Abstract/Free Full Text]

  14. King PD, Katz DR. Mechanisms of dendritic cell function. Immunol Today 1990;11:206–211.[Medline]

  15. Caux C, Liu YJ, Banchereau J. Recent advances in the study of dendritic cells and follicular dendritic cells. Immunol Today 1995;16:2–4.[Medline]

  16. Steinman RM. The dendritic cell system and its role in immunogenicity. Ann Rev Immunol 1991;9:271–296.[Medline]

  17. MacPherson GG. Life history and function of dendritic cells. In: Human Monocytes. Orlando, FL: (Harcourt Brace & Co.): Academic Press, 1989:79-88.

  18. Leenaerts PL, Ceuppens JL, Van Damme J et al. Evidence that stimulator cell-derived IL-6 and IL-1 are released in the mixed lymphocyte culture but are not requisite for responder T cell proliferation. Transplant 1992;54:1071–1078.[Medline]

  19. De Wit H, Esselink MT, Halie MR et al. Differential regulation of M-CSF and IL-6 gene expression in monocytic cells. Br J Haematol 1994;86:259–264.[Medline]

  20. Santiago-Schwarz F, Fleit HB. Identification of nonadherent mononuclear cells in human cord blood that differentiates into macrophages. J Leukoc Biol 1988;43:51–59.[Abstract]

  21. Rosenzwajg M, Canque B, Yagello M et al. In vitro differentiation of dendritic cells from CD34+ progenitor cells. J Cell Biochem 1995;S21A:C1–120.

  22. Mooij P, Simons PJ, de Haan-Meulman M et al. Effect of thyroid hormones and other iodinated compounds on the transition of monocytes into veiled/dendritic cells: role of granulocyte-macrophage colony-stimulating factor, tumor-necrosis factor-{alpha} and interleukin-6. J Endocrinol 1994;140:503–512.[Abstract/Free Full Text]

  23. Schreiber S, Kilgus O, Payer E et al. Cytokine pattern of Langerhans cells isolated from murine epidermal cell cultures. J Immunol 1992;149:11:3525–3534.

  24. Bohbot A, Eischen A, Felden C et al. U937 cell line: impact of CSFs, IL-6 and IFN-{gamma} on the differentiation and the Leu-CAM proteins expression. Exp Hematol 1993;21:564–572.[Medline]

  25. Buchsbaum ME, Kupper TS, Murphy GF. Differential induction of intercellular adhesion molecule-1 in human skin by recombinant cytokines. J Cutan Pathol 1993:20:21–27.[Medline]

  26. Førre Ø, Waalen J, Thoen J et al. Macrophages and dendritic cells in rheumatic disease. In: Gupta S, ed. Immunol Rheum Disease. New York: Plenum Press, 1985:5453-5462.

  27. Knight SC. Dendritic cells in inflammatory joint disease. In: Goodacre J, Carson D, eds. Immunopathogenetic Mechanisms of Arthritis. Boston, MA: Lancaster MTP Press, 1988:69-85.

Received September 12, 1995; accepted for publication November 15, 1995.




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