Interleukin-12 release by mitogen-stimulated mononuclear cells in the elderly
Introduction
Deterioration of immune function in old age is a common finding. This progressive decline of the immune system, defined `immunosenescence' (Pawelec et al., 1997), is one of the several physiologic changes thought to occur during mammalian ageing. Weakening of T cell activity in old patients is in vivo clearly shown by decreased delayed type hypersensitivity tests to recall antigens as well as by immunization procedures in which T-cell dependent antibody production is defective (Thoman and Weigle, 1989, Song et al., 1993). These age-related changes are clearly evident in the peripheral T cell pool. Age-associated changes of Th1-like or Th2-like cytokine production (Romagnani, 1995) by CD4-positive T cells are clearly demonstrated (Hobbs et al., 1991, Pawelec, 1995). We have previously reported that production of some Th1-like cytokines by mitogen-stimulated peripheral blood mononuclear cells (PBMNC) is reduced in elderly (Candore et al., 1993, Caruso et al., 1996). The mechanisms involved in the age related Th1-like cytokine impairment are not completely understood although changes in intra- and intercellular signaling impairment might be involved.
Interleukin-12 (IL-12) is now considered the key cytokine for the induction of a Th1-type response. One of most important effect of IL-12 is the strong enhancement of interferon-γ (IFN-γ) synthesis by T and natural killer (NK) cells (Chan et al., 1992). In addition, IL-12 activates both T and NK cytotoxic activity (Gately et al., 1992), playing a major role in defense against parasitic and viral infections (Afonso et al., 1994, Orange et al., 1995). The well documented increased susceptibility of elderly individuals to various infectious and neoplastic diseases might be so related to an impairment of IL-12 production with a lack of the optimal conditions for Th1-like cytokine synthesis (Candore et al., 1993).
To evaluate IL-12 involvement in the elderly related immune dysfunction, the cytokine production by PBMNC from old and young subjects stimulated with non-T mitogens (bacterial lipopolysaccharide, LPS) and T-dependent (phytoemagglutinin, PHA; immobilized anti-CD3 monoclonal antibodies, anti-CD3) mitogens was evaluated.
Section snippets
Subjects
Fifteen old Sicilians were studied (eight women and seven men, range 66–84 years). None of the selected subjects was affected by neoplastic, infectious or autoimmune disease, not received any drug influencing immune functions at the time of the study. As a control, 12 staff laboratory healthy Sicilians (six women and six men, range 21–40 years) were studied.
Cell cultures
PBMNC from old and young subjects were isolated by centrifugation on Ficoll-Hipaque gradient (Nycomed As, Diagnostic, Oslo, Norway) and
IL-12 production by stimulated mononuclear cells
IL-12 production by either unstimulated or stimulated PBMNC cultures from old and young individuals was analyzed at 48 h (Table 1). Supernatants from the all in vitro cultures, stimulated with PHA, immobilized anti-CD3, or LPS, contained increased cytokine concentrations respect to unstimulated ones. IL-12 production by PHA stimulated mononuclear cells from old subjects was significantly reduced when compared to that from young ones. Similar results were obtained using immobilized anti-CD3
Discussion
We have recently reported that besides IL-2 and soluble form of its receptor, also the ability to produce IFN-γ was impaired in mitogen-stimulated T cells from old healthy subjects, whereas the cell capability to produce IL-4 and IL-6 was not affected (Caruso et al., 1991, Candore et al., 1992, Candore et al., 1993). Since IL-12 plays a major role in the induction of Th1-like response and particularly in the IFN-γ production (Kubin et al., 1994), in this study we have evaluated IL-12 production
Acknowledgements
This work was supported by grants from MURST, Rome (60%) to C.C. and D.L. and C.N.R., Rome to C.C.
References (38)
- et al.
The effect of age on mitogen responsive T cell precursors in human beings is completely restored by interleukin-2
Mech. Ageing Develop.
(1992) - et al.
Soluble interleukin-2 receptor secretion defect in vitro in elderly subjects
Mech. Ageing Develop.
(1991) - et al.
Evidence of enhanced type 2 immune response and impaired upregulation of a type 1 response in frail elderly nursing home resident
Mech. Ageing Develop.
(1997) - et al.
Regulation of human cytolytic lymphocyte response by IL-12
Cell. Immunol.
(1992) - et al.
In vitro T-cell activation in elderly individuals: failure in CD69 and CD71 expression
Mech. Ageing Develop.
(1996) - et al.
The T-cell in the ageing individual
Mech. Ageing Develop.
(1997) Molecular and cell biological studies of ageing and their application to considerations of T lymphocyte immunosenescence
Mech. Ageing Develop.
(1995)- et al.
Age related effects in T-cell activation and proliferation
Exp. Gerontol.
(1993) - et al.
The cellular and subcellular bases of immunosenescence
Adv. Immunol.
(1989) - et al.
Induction and regulation of NFkB during aging: role of protein kinases
Clin. Immunol. Immunopathol.
(1996)
Impairment of signal transduction in T-cells from old mice
Mech. Ageing Develop.
Age related decreases in IL-2 production by human T-cells are associated with impaired activation of nuclear transcriptional factors AP-1 and NF-AT
Cell. Immunol.
The adiuvant effect of interleukin-12 in a vaccine against Leishmania Major
Science
The CD40 antigen and its ligand
Annu. Rev. Immunol.
γ-Interferon, interleukin-4 and interleukin-6 in vitro production in old subjects
Autoimmunity
Cytokine production pathway in elderly
Immunol. Res.
Mechanisms of IFN-γ induction by natural killer cell stimulatory factor (NKSF/IL-12). Role of trascription and mRNA stability in the synergistic interaction between NKSF and IL-2
J. Immunol.
Production of natural killer cell stimulatory factor (interleukin-12) by peripheral blood mononuclear cells
J. Exp. Med.
Age related increase of CD45RO+ lymphocytes in physically active adults
Eur. J. Immunol.
Cited by (36)
Models of immune aging
2018, Conn's Handbook of Models for Human AgingImmunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter?
2017, Cancer Treatment ReviewsThe role of immunity in elderly cancer
2010, Critical Reviews in Oncology/HematologyCitation Excerpt :The inhibitory effects of IL-10 on the accessory functions of APCs, includes the conversion of immature DCs into tolerating APCs, the suppression of IL-12 production by activated DCs, the down-regulation of CD40 expression on DCs from elderly subjects [112]. Moreover the production of cytokines important for the differentiation and functional activity of APCs, like IL-4 and IL-12, declines in exhausted elderly people [113]. As a result age-related changes in cytokine levels may not only directly influence immune responses but may also alter the balance and maturation of APC subsets.
Enhancement of cytotoxic T-lymphocyte response in aged mice by a novel treatment with recombinant AdIL-12 and wild-type adenovirus in rapid succession
2008, Molecular TherapyCitation Excerpt :It has been proposed that defective migration of dendritic cells to the draining lymph nodes may be in part responsible for impaired adaptive immune response in aged mice.35,36 A reduced expression level of CD40L on the activated CD4 T cells was found in aged human individuals,37,38 which in turn led to reduced IL-12 secretion.39,40 At the cellular level, the expression of the effector molecules granzyme and perforin was lower in senescent CTLs.41
The effect of IL-12 on clinical and laboratory aspects of experimental SLE in young and aging mice
2003, Experimental Gerontology