Development of interleukin-12-producing capacity throughout childhood
Open accessAbstract
Increasing evidence indicates that the capacity to induce protective Th1 immune responses is impaired in early childhood, an observation that can be partially attributed to deficiencies in antigen-presenting-cell function. Synthesis of interleukin 12 (IL-12), a key Th1-trophic cytokine, is markedly reduced in the neonatal period, though there is a paucity of knowledge concerning the ontogeny of IL-12-synthetic capacity throughout the childhood years. Hence, we examined the production of bioactive IL-12 p70 by circulating mononuclear cells in a population of healthy individuals. As expected, the capacity to synthesize IL-12 p70 in response to either lipopolysaccharide or heat-killed Staphylococcus aureus was markedly impaired at birth, even after priming of cells with gamma interferon. Surprisingly however, IL-12 p70 synthesis by peripheral blood mononuclear cells from both 5- and 12-year-old children was still substantially below that seen in adults, and this did not appear to be related to excessive production of IL-10. In contrast, dendritic cells from adults and neonates, derived from monocytes with granulocyte-macrophage colony-stimulating factor and IL-4, synthesized equivalent amounts of IL-12 p70 in response to microbial stimulation. This indicates that the impaired capacity for IL-12 synthesis in childhood is not an intrinsic property of circulating mononuclear cells but rather can be readily overcome in response to appropriate maturational stimuli. Because IL-12 arose predominantly from circulating HLA-DR+cells that lacked B-cell- and monocyte-specific markers, we propose that the slow maturation of IL-12-synthetic capacity in the childhood years can be attributed to deficiencies in the number and/or function of dendritic cells.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PBMC production of IL-12 in response to bacterial challenge increases with age, but stimulated production of IL-12 by 12 years of age is still substantially lower than in adults.
“In a study of infants, 5-year-olds, 12-year-olds, and adults, PBMC production of IL-12 in response to bacterial challenge was shown to increase with age; however, stimulated production of IL-12 by 12 years of age was still substantially lower than in adults (Upham et al., 2002).”
From Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease (2017) · cites this paper as Upham et al., 2002
Innate immunity continues to mature through childhood.
“Innate immunity continues to mature through childhood, although few studies directly test this.”
From Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease (2017) · cites this paper as Upham et al., 2002
Cites
Proliferating dendritic cell progenitors in human blood.
Romani, N., Grüner, S., Brang, D., Kämpgen, E., Lenz, A., Trockenbacher, B., Konwalinka, G., Fritsch, P. O., Steinman, R. M., & Schuler, G. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.180.1.83 · Cited by 1,841 · see citing works
D’Andrea, A., Rengaraju, M., Valiante, N. M., Chehimi, J., Kubin, M. Z., Aste-Amézaga, M., Chan, S. H., Kobayashi, M., Young, D., & Nickbarg, E. (1992) · The Journal of Experimental Medicine · doi:10.1084/jem.176.5.1387 · Cited by 1,143 · see citing works
Prescott, S. L., Macaubas, C., Holt, B. J., Smallacombe, T. B., Loh, R., Sly, P. D., & Holt, P. G. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.10.4730 · Cited by 778 · see citing works
Self-citationNeonatal Tolerance Revisited: Turning on Newborn T Cells with Dendritic Cells
Ridge, J. P., Fuchs, E. J., & Matzinger, P. (1996) · Science · doi:10.1126/science.271.5256.1723 · Cited by 767 · see citing works
Induction of T H 1 and T H 2 Immunity in Neonatal Mice
Forsthuber, T. G., Yip, H. C., & Lehmann, P. (1996) · Science · doi:10.1126/science.271.5256.1728 · Cited by 684 · see citing works
Marchant, A., Goetghebuer, T., Ota, M. O. C., Wolfe, I., Ceesay, S. J., Groote, D. D., Corrah, T., Bennett, S., Wheeler, J., Huygen, K., et al. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.4.2249 · Cited by 404 · see citing works
Histamine Potently Suppresses Human IL-12 and Stimulates IL-10 Production via H2 Receptors
Elenkov, I. J., Webster, E., Papanicolaou, D. A., Fleisher, T. A., Chrousos, G. P., & Wilder, R. L. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.5.2586 · Cited by 367 · see citing works
Deficient IL-12(p35) Gene Expression by Dendritic Cells Derived from Neonatal Monocytes
Goriely, S., Vincart, B., Stordeur, P., Vekemans, J., Willems, F., Goldman, M., & Wit, D. D. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.3.2141 · Cited by 349 · see citing works
Phenotypic and functional immaturity of human umbilical cord blood T lymphocytes.
Harris, D. T., Schumacher, M. J., Locascio, J. J., et al. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.21.10006 · Cited by 349 · see citing works
Wilson, C. B., Westall, J., Johnston, L. A., et al. (1986) · Journal of Clinical Investigation · doi:10.1172/jci112383 · Cited by 302 · see citing works
Yap, G. S., Pesin, M., & Sher, A. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.2.628 · Cited by 298 · see citing works
Barrios, C. S., Brawand, P., Berney, M., et al. (1996) · European Journal of Immunology · doi:10.1002/eji.1830260713 · Cited by 279 · see citing works
Genetic ‘risk’ for atopy is associated with delayed postnatal maturation of T‐cell competence
Holt, P. G., CLOUGH, J. B., Holt, B. J., BARON‐HAY, M. J., Rose, A. H., Robinson, B. W. S., & Thomas, W. R. (1992) · Clinical & Experimental Allergy · doi:10.1111/j.1365-2222.1992.tb00135.x · Cited by 269 · see citing works
Self-citationIL-12 induces the production of IFN-gamma by neonatal human CD4 T cells.
Wu, C. Y., Demeure, C. E., Kiniwa, M., Gately, M. K., & Delespesse, G. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.151.4.1938 · Cited by 222 · see citing works
Lee, S., Suen, Y., Chang, L.-J., Bruner, V., Qian, J. X., Indes, J., Knoppel, E., van de Ven, C., & CAIRO, M. S. (1996) · Blood · doi:10.1182/blood.v88.3.945.945 · Cited by 191 · see citing works
Studies of human cord blood dendritic cells: evidence for functional immaturity
Hunt, D., Huppertz, H., Jiang, H., & Petty, R. (1994) · Blood · doi:10.1182/blood.v84.12.4333.bloodjournal84124333 · Cited by 187 · see citing works
Taylor, S. M., & Bryson, Y. J. (1985) · The Journal of Immunology · doi:10.4049/jimmunol.134.3.1493 · Cited by 166 · see citing works
Martínez, X., Brandt, C., Saddallah, F., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.16.8726 · Cited by 165 · see citing works
Adkins, B., & Du, R.-Q. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.9.4217 · Cited by 159 · see citing works
Maturation of human neonatal CD4+ and CD8+ T lymphocytes into Th1/Th2 effectors
Delespesse, G., Yang, L. P., Ohshima, Y., Demeure, C. E., Shu, U., Byun, D., & Sarfati, M. (1998) · Vaccine · doi:10.1016/s0264-410x(98)00101-7 · Cited by 142 · see citing works
Adkins, B., Bu, Y., & Guevara‐Ramírez, P. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.2.918 · Cited by 135 · see citing works
Identification of Cord Blood Dendritic Cells as an Immature CD11c− Population
Sorg, R. V., Kögler, G., & Wernet, P. (1999) · Blood · doi:10.1182/blood.v93.7.2302 · Cited by 132 · see citing works
Hemmann, S., Nikolaizik, W. H., Schöni, M. H., Blaser, K., & Crameri, R. (1998) · European Journal of Immunology · doi:10.1002/(sici)1521-4141(199804)28:04 · Cited by 130 · see citing works
Rowe, J., Macaubas, C., Monger, T., Holt, B. J., Harvey, J., POOLMAN, J. T., Sly, P. D., & Holt, P. G. (2000) · Infection and Immunity · doi:10.1128/iai.68.7.3873-3877.2000 · Cited by 125 · see citing works
Self-citationRegulation of T‐helper cell responses to inhalant allergen during early childhood
Macaubas, Sly, P. D., Burton, Tiller, Yabuhara, Holt, P. G., Smallacombe, Kendall, Jenmalm, M. C., & Holt, P. G. (1999) · Clinical & Experimental Allergy · doi:10.1046/j.1365-2222.1999.00654.x · Cited by 124 · see citing works
Self-citationRowe, J., Macaubas, C., Monger, T., Holt, B. J., Harvey, J., POOLMAN, J. T., Loh, R., Sly, P. D., & Holt, P. G. (2001) · The Journal of Infectious Diseases · doi:10.1086/320996 · Cited by 123 · see citing works
Self-citationBarrios, C. S., Brandt, C., Berney, M., et al. (1996) · European Journal of Immunology · doi:10.1002/eji.1830261118 · Cited by 118 · see citing works
Hypomethylation of the interferon‐γ gene correlates with its expression by primary T‐lineage cells
Melvin, A. J., McGurn, M. E., Bort, S. J., Gibson, C., & Lewis, D. B. (1995) · European Journal of Immunology · doi:10.1002/eji.1830250218 · Cited by 114 · see citing works
Ausiello, C. M., Lande, R., Urbani, F., la Sala, A., Stefanelli, P., Salmaso, S., Mastrantonio, P., & Cassone, A. (1999) · Infection and Immunity · doi:10.1128/iai.67.8.4064-4071.1999 · Cited by 103 · see citing works
Analysis of Neonatal T Cell and Antigen Presenting Cell Functions
Trivedi, H. N., HayGlass, K. T., Gangur, V., et al. (1997) · Human Immunology · doi:10.1016/s0198-8859(97)00202-4 · Cited by 94 · see citing works
Zola, H., Fusco, M. J., Macardle, P. J., et al. (1995) · Pediatric Research · doi:10.1203/00006450-199509000-00021 · Cited by 73 · see citing works
Bont, L., Kavelaars, A., Heijnen, C. J., van Vught, A. J., & Kimpen, J. L. L. (2000) · The Journal of Infectious Diseases · doi:10.1086/315433 · Cited by 68 · see citing works
CD14-independent responses to LPS require a serum factor that is absent from neonates
Cohen, L., Haziot, A., Shen, D., et al. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.11.5337 · Cited by 65 · see citing works
Joyner‐Matos, J., Augustine, N. H., Taylor, K. A., et al. (2000) · The Journal of Infectious Diseases · doi:10.1086/315796 · Cited by 58 · see citing works
Scott, M. E., Kubin, M. Z., & Kohl, S. (1997) · Pediatric Research · doi:10.1203/00006450-199704000-00015 · Cited by 54 · see citing works
Matthews, N. C., Wadhwa, M., Bird, C., Borràs, F. E., & Navarrete, C. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.12.6206 · Cited by 47 · see citing works
Elliott, S. R., Macardle, P. J., & Zola, H. (1998) · Journal of Immunological Methods · doi:10.1016/s0022-1759(98)00111-2 · Cited by 17 · see citing works
Ansart‐Pirenne, H., Soulimani, N., Tartour, É., et al. (1999) · Pediatric Research · doi:10.1203/00006450-199903000-00020 · Cited by 14 · see citing works
Differential Control of Neonatal Tolerance by Antigen Dose versus Extended Exposure and Adjuvant
Min, B., Legge, K. L., Caprio, J. C., et al. (2000) · Cellular Immunology · doi:10.1006/cimm.2000.1618 · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Basha, S., Surendran, N., & Pichichero, M. (2014) · Expert Review of Clinical Immunology · doi:10.1586/1744666x.2014.942288 · Cited by 513 · see citing works
Newton, S. M., Brent, A. J., Anderson, S., Whittaker, E., & Kampmann, B. (2008) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(08)70182-8 · Cited by 480 · see citing works
Unique aspects of the perinatal immune system
Zhang, X., Zhivaki, D., & Lo-Man, R. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.54 · Cited by 276 · see citing works
An exposome perspective: Early-life events and immune development in a changing world
Renz, H., Holt, P. G., Inouye, M., Logan, A. C., Prescott, S. L., & Sly, P. D. (2017) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2017.05.015 · Cited by 226 · see citing works
Self-citationKuhlman, K. R., Chiang, J. J., Horn, S., & Bower, J. E. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.05.020 · Cited by 208 · see citing works
“In a study of infants, 5-year-olds, 12-yearolds, and adults, PBMC production of IL-12 in response to bacterial challenge was shown to increase with age; however, stimulated production of IL-12 by 12 years of age was still substantially lower than in adults (Upham et al., 2002).”
Yang, L. L., Stiernborg, M., Skott, E., Xu, J., Wu, Y., Landberg, R., Arefin, S., Kublickiene, K., Millischer, V., Nilsson, I. A. K., et al. (2023) · Nutrients · doi:10.3390/nu15051293 · Cited by 42 · see citing works
- Authors
- Upham, J. W., Lee, P. T., Holt, B. J., Heaton, T., Prescott, S. L., Sharp, M. J., Sly, P. D., & Holt, P. G.
- Affiliations
- The Kids Research Institute Australia (AU)
- Corresponding author
- Upham, John W.
- Venue
- Infection and Immunity
- Publisher
- American Society for Microbiology
- Published
- 2002-12
- Volume
- 70
- Issue
- 12
- Pages
- 6583-6588
- ISSN
- 0019-9567 (ISSN-L)
- 1098-5522
- PMC
- PMC133015
- OpenAlex
- W1978116307
- Cited by
- 257
- References
- 39
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 3 · 2019: 5 · 2018: 7 · 2017: 14 · 2016: 13 · 2015: 8 · 2014: 17 · 2013: 11 · 2012: 11
- FWCI
- 5.60
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Infection and Immunity (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Health and Medical Research Council
- National Medical Research Council
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- IL-12, IL-12p70, ontogeny, childhood, Th1 response, dendritic cells, dendritic cell maturation, antigen-presenting cells, HLA-DR+ cells, lipopolysaccharide, Staphylococcus aureus, interferon-gamma, IL-10, mononuclear cells, monocyte-derived dendritic cells
- MeSH terms
- Adult, Aging, Child, Child, Preschool, Dendritic Cells, Fetal Blood, Hot Temperature, Humans, Infant, Newborn, Leukocytes, Mononuclear, Lipopolysaccharides, Monocytes, Staphylococcus aureus, Interleukin-10, Interleukin-12
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
