Interleukin-2 (IL-2) is a prototypical T cell growth factor and immunoregulatory cytokine produced by T lymphocytes, dendritic cells, and microglia [1], [2]. IL-2 plays a pivotal role in regulating immunological homeostasis, and alterations in IL-2 functioning have been suggested to modify susceptibility to autoimmunity. Several studies indicate that IL-2 and IL-2 receptor levels increase in serum and cerebrospinal fluid of MS patients and an active immune mechanism involving IL-2 production takes place within the central nervous system [3]. It has been also reported that levels of IL-2 and IL-2 mRNA increase in the CNS during the induction and acute phases of disease, and decrease through the recovery phase [4], [5]. The role of IL-2 in EAE may be influenced by its direct effects on glial cells [6]. Studies also show that IL-2 gene deletion produces a robust reduction in susceptibility to EAE in C57BL/6 mice [7], [8].

Human neuropathological studies discloses that IL-2 immunoreactivity is present in perinatal brain lesions [9]. However, little is known about the triggering factors and the cellular sources of IL-2 in brains. Several studies indicate that among brain cells, microglia are major producer of IL-2 in response to LPS [10], [11]. Subgroups of neurons have been shown in vivo to produce IL-2. In contrast, naive or LPS-stimulated astrocytes in culture from neonatal rat brain do not produce any IL-2 transcripts [12].

IL-12 plays a critical role in the early inflammatory response to infection and in the generation of Th1 cells [13], [14], [15], [16], [17] to favor cell-mediated immunity. It has been found that over-production of IL-12 can be dangerous to the host because it is involved in the pathogenesis of a number of autoimmune inflammatory diseases (e.g. MS, arthritis, type 1 diabetes, etc.). IL-12 consists of a heavy chain (p40) and a light chain (p35) linked covalently by disulfide bonds to give rise to the so-called bioactive heterodimeric (p35:p40 or p70) molecule [16], [18], [19]. Recently, p40 has been shown to pair with p19 to form a newly discovered cytokine, IL-23. IL-23 has biological functions that are similar to as well as distinct from IL to 12. For example, similar to IL-12, IL-23 also enhances the proliferation of Th1 cells and increases their IFN-γ production [16], [20], [21], [22]. Apart from forming heterodimers (IL-12 and IL-23), the p40 subunit is also secreted as monomer (p40) and homodimer (p402) [18], [23], [24], [25], [26], [27], [28]. Because all these cytokines (IL-12, IL-23, p40, and p402) contain the common p40 subunit, these molecules can logically be grouped into the p40 family of cytokines [14].

In contrast, the role of p402 and p40 in the disease process of EAE and MS was not recognized. It was known that p402 was inhibitory to bioactive cytokine IL-12 and/or biologically inactive until we demonstrated the induction of NO synthase (iNOS) and TNFα by p402 in microglia and macrophages [25], [29]. We have demonstrated that p402, but not IL-12, induces the expression of IL-16, a leukocyte chemoattractant factor, in microglia and macrophages [28]. Furthermore, we have also reported that p402, but not IL-12, is capable of inducing the expression of lymphotoxin α in various immune cells [27]. By using neutralizing mAb against mouse p402 [23], we have demonstrated that selective neutralization of p402 protects mice from EAE [30].

Here, we describe how p402 is endowed with another novel biological function. Interestingly, we report that among the p40 family, p402 is the strongest inducer of the expression of IL-2 in microglia and macrophages. Moreover, functional blocking of p402 by mAb a3-1d decreased the level of IL-2 in T cells and microglia and protected mice from relapsing-remitting EAE. These results further emphasize that p402 is biologically active and suggest that p402 may be considered as a separate cytokine with biological functions distinct from other members of the p40 family.