INTERLEUKIN-2 AND HUMAN MONOCYTE ACTIVATION

The recognition of the monocyte/macrophage-activating properties of IL-2 has broadened our image of the biological effects of this lymphokine from those of a T cell growth factor to those of a molecule with pleiotropic effects. The detailed analysis of the mechanisms of action of IL-2 including its biological effects on different cell types and the regulation of its receptors has increased dramatically the spectrum of the biological responses that can be modified by IL-2. The regulation of the expression of the IL-2 receptor subunits differs in terms of response to extracellular stimuli and intracellular control, suggesting that the response to IL-2 will vary depending on the nature and extent of environmental stimulation. Furthermore, the fact that the IL-2Rγ chain can be part of the receptor for IL-4, IL-7, and perhaps other cytokines indicates that IL-2 may modulate the response of monocytes simply by binding or releasing the IL-2Rγ chain and thus modulating the responsiveness to IL-4 or IL-7. Conversely, the extent of utilization of IL-2Rγ chain by various cytokines may dictate the monocytic response to IL-2. In fact, the availability of IL-2Rγ chain seems to be the limiting factor in the response of monocytes to IL-2. Modulation of cytokine receptors is an integral part of the control of the IL-2 response. The induction of CSF-1 receptor by IL-2 and the positive effect of CSF-1 on the duration of the cytotoxic response in IL-2-stimulated monocytes are an interesting example of a synergistic interaction of potential physiological relevance. The response of monocytes to IL-2 can also be modulated by inhibitory circuits, such as those involving TGF-β1, IFN-γ, and IL-4. However, IFN-γ and IL-4 can also activate monocytes and the timing and relative concentrations of the various cytokines may be critical variables in determining the ultimate monocyte phenotype. These studies have given us a glimpse of a very complex picture composed of multiple backgrounds and several players. However, the present information is not sufficient to make meaningful predictions of the resulting monocyte phenotype in an inflammatory reaction in which multiple cytokines are involved. It will be important to determine experimentally the relevance of each variable in the activation of monocytes in vivo and at the same time to develop comprehensive theoretical models to organize the existing information into propositions and hypotheses useful for predicting and focusing the investigation of the phenotype of mononuclear phagocytes in pathological situations. With sufficient understanding, it may be possible to inhibit monocytes when their function is contributory to a pathological state and stimulate them when their function might eradicate a pathological state. The central role of monocytes in medicine that was foreseen for them by George Bernard Shaw in 'The Doctor's Dilemma' early in the twentieth century has certainly not come to pass. However, we may soon have enough information to offer monocytes a screen test for that role.