Abstract
Cytokines interleukin (IL)-12 and IL-23 are implicated in the pathogenesis of psoriasis. IL-12 causes differentiation of CD4+ T cells to interferon-gamma (IFN-gamma)-producing T helper 1 (Th1) cells, while IL-23 induces differentiation to IL-17-producing pathogenic Th17 cells. The effects of the monoclonal antibody to IL-12/23 p40 subunit (CNTO 1275) on IL-12 receptor (IL-12R) expression, markers associated with skin homing, activation, and cytokine secretion were investigated in vitro using human peripheral blood mononuclear cells (PBMCs) from healthy donors. PBMCs were activated in the presence or absence of recombinant human (rh) IL-12 or rhIL-23, with or without CNTO 1275. CNTO 1275 inhibited upregulation of CLA, IL-12R, IL-2Ralpha and CD40L expression and also inhibited IL-12- and IL-23-induced IFN-gamma, IL-17A, tumor necrosis factor (TNF)-alpha, IL-2, and IL-10 secretion. Thus, the therapeutic effect of CNTO 1275 may be attributed to the IL-12/23 neutralization, resulting in decreased expression of skin homing and activation markers, and IL-12- and IL-23-induced cytokine secretion.
MeSH terms
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Antibodies, Monoclonal / metabolism
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Monoclonal, Humanized
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Antigens, Differentiation, T-Lymphocyte
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Antigens, Neoplasm / drug effects
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism*
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / metabolism
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CD40 Ligand / drug effects
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CD40 Ligand / metabolism*
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Cell Culture Techniques
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Cytokines / metabolism*
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Down-Regulation
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Humans
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Immunologic Factors / metabolism
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Interferon-gamma / genetics
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Interferon-gamma / metabolism
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Interleukin-12 / genetics
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Interleukin-12 / immunology
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Interleukin-12 Receptor beta 1 Subunit / genetics
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Interleukin-12 Receptor beta 1 Subunit / metabolism
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Interleukin-12 Receptor beta 2 Subunit / genetics
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Interleukin-12 Receptor beta 2 Subunit / metabolism
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Interleukin-12 Subunit p40 / metabolism
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Interleukin-17 / genetics
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Interleukin-17 / metabolism
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Interleukin-2 Receptor alpha Subunit / genetics
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Interleukin-2 Receptor alpha Subunit / metabolism
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Interleukin-23 Subunit p19 / metabolism
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Interleukins / metabolism*
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Lymphocyte Activation
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Membrane Glycoproteins / drug effects
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Receptors, Interleukin / drug effects
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Receptors, Interleukin / metabolism*
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Receptors, Interleukin-12 / genetics
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Receptors, Interleukin-12 / metabolism
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Th1 Cells / drug effects
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Tumor Necrosis Factor-alpha / metabolism
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Up-Regulation / drug effects
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Ustekinumab
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antigens, Differentiation, T-Lymphocyte
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Antigens, Neoplasm
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CTAGE1 protein, human
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Cytokines
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Immunologic Factors
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Interleukin-12 Receptor beta 1 Subunit
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Interleukin-12 Receptor beta 2 Subunit
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Interleukin-12 Subunit p40
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Interleukin-17
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Interleukin-2 Receptor alpha Subunit
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Interleukin-23 Subunit p19
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Interleukins
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Membrane Glycoproteins
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Receptors, Interleukin
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Receptors, Interleukin-12
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Tumor Necrosis Factor-alpha
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CD40 Ligand
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Interleukin-12
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Interferon-gamma
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Ustekinumab