Interpreting mixed signals: the cell's cytokine conundrum

Abstract

Cytokines are essential for the activation, differentiation and control of the immune system. Many cytokines, alone or in combination with other cytokines, have multiple functions and can often act on many different cell types with distinct developmental or functional consequences. Despite the myriad of cytokines and cytokine receptors, there are relatively few signaling molecules that transduce these diverse cytokine signals. In this review, we will discuss the potential mechanisms used by cytokines to mediate distinct cellular outcomes from a small number of signaling molecules. Understanding this paradigm in cytokine signaling can aid in the development of potential therapeutic approaches involving cytokine targeting or use.

Figure 1

STAT modifications. STATs can be modified by many mechanisms; JAK-dependent tyrosine phosphorylation primes dimerization and allows for nuclear entry. Serine phosphorylation occurs via secondary signaling pathways such as Akt-mTOR or MAPK and permits alternative transcriptional programs. SUMOylation can inhibit certain transcriptional programs while sparing others. Acetylation is a controversial modification that may affect dimerization or nuclear import.

Figure 2

STAT3 signaling in T cells. Many cytokines utilize STAT3 to transduce their signals in cells. Despite the fact that all these cytokines utilize STAT3, the outcome of these cytokine signals is distinct between them. This variation can occur at the level of the receptor, at the level of negative regulation (such as SOCS3), or further downstream at the level of gene accessibility. Regarding the ‘Other STATs activated’ note that not all of these pathways have been evaluated genetically to confirm their roles in cytokine function.