Interleukin-2 and human monocyte activation
Authors: Espinoza-Delgado Igor , Bosco Maria Carla , Musso Tiziana , Gusella G Luca , Longo Dan L , Varesio Luigi 
Published: January 2018

Abstract
Metchnikoff first described mononuclear phagocytic cells at the end of the last century and proposed their critical involvement in the host immune defense. Since then, an impressive body of literature has documented the involvement of monocytes in the immune response as immunomodulating cells [1, 2], antigen-presenting cells [3], and effector cells [1, 4–7]. Human monocytes can be induced to express new or augmented biological functions in a process generally referred to as activation. The expression of the activated phenotype in monocytes is transient and, in contrast to that of other immune cells such as lymphocytes or natural killer (NK) cells, it is not associated with proliferation. Monocyte proliferation, occurring primarily in the bone marrow [8–10], maintains an adequate supply of circulating monocytes ready to extravasate to the tissues in response to physiological or pathological stimuli. The recognition that proliferation is not part of the genetic program of monocyte activation poses interesting questions about the function and biology of growth factor receptors on these cells. Monocytes express receptors for a variety of growth factors that are either monocyte lineage specific, such as the macrophage colony-stimulating factor (CSF-1) receptor [11, 12]; shared with other cell lineages, such as the granulocyte-macrophage CSF (GM-CSF) receptor [13]; or typical of other lineages, such as the interleukin-2 receptor (IL-2R) [14–16]. However, monocytes respond to stimulation by growth factors not with proliferation but with functional changes. Two remarkable examples are CSF-1 and IL-2. CSF-1 induces proliferation of monocyte precursors in the bone marrow [17], but it promotes survival [18], migration [19], cytokine secretion [20], and cytotoxic responses [21] in circulating monocytes. IL-2, originally described as a T cell growth factor [22], is a powerful activator of human monocytes. Fresh human monocytes respond to IL-2 with microbicidal [23] and tumoricidal activities [1, 4–7], cytokine [24–28] and growth factor [29–31] production, and expression of growth factor receptors [21, 32]. We will discuss the effects of IL-2 on human monocytes, the differential expression and modulation of the IL-2R subunits, and their relationship with the responsiveness of monocytes to IL-2. Finally, we will briefly discuss the regulation of IL-2–induced monocyte activation by inhibitory signals. IL-2 can also activate murine macrophages. However, we will limit our discussion to the human monocyte system. 33–35], tumor necrosis factor α (TNF-α) [25, 28], interleukin-6 (IL-6) [26], and interleukin-8 (IL-8) [27]. TNF-α and IL-β are inflammatory mediators cytotoxic or cytostatic for tumor cells, whose involvement in the acute-phase response and in monocyte antitumor activity has been reviewed [36–38]. Monocytes are the predominant source of IL-6 and IL-8 in peripheral blood [26, 39], although other cell types contribute to the IL-6 and IL-8 levels [26, 40–42]. IL-8 induces chemotaxis in basophils, neutrophils, and T lymphocytes [43–47] and is member of the family of chemoattractant cytokines now called chemokines (for a review see ref. 48). IL-6 is a pleiotropic cytokine whose biological activities include regulation of the acute-phase response [37, 49], stimulation of multipotent colony formation of hematopoietic stem cells [50], induction of immunoglobulin production [51], and induction of T cell growth and cytotoxic T lymphocyte differentiation [52, 53]. IL-8 and IL-6 induction by IL-2 occurs at the transcriptional level. The promoter of both genes contains a consensus sequence for the nuclear transactivator complex NF-χB [54, 55]. The observation that IL-2 increases the expression of NF-χB complexes in the nucleus of monocytes suggests that NF-χB may be involved in the transcriptional activation of IL-8 and IL-6 genes by IL-2 (T. Musso et al., unpublished observation). Secretion of IL-6 and IL-8 is a specific response to IL-2 and not a general response to activating stimuli, because interferon-γ (IFN-γ), which is also a potent monocyte activator, inhibits rather than induces IL-6 or IL-8 production [26, 27]. IL-2 stimulates IL-6 and IL-8 production both directly and indirectly by inducing IL-1β and TNF-α secretion, which, in turn, stimulates the expression of IL-8 and IL-6 [26, 56]. The indirect response to IL-2 represents an amplifying loop that is delayed with respect to direct stimulation and that may be important in allowing prolonged production of IL-6 or IL-8 during an inflammatory response.