Cytokine signaling modules in inflammatory responses

Abstract

Cytokine signaling via a restricted number of Jak-Stat pathways positively and negatively regulates all cell types involved in the initiation, propagation, and resolution of inflammation. Here, we focus on Jak-Stat signaling in three major cell types involved in inflammatory responses: T cells, neutrophils, and macrophages. We summarize how the Jak-Stat pathways in these cells are negatively regulated by the Suppressor of cytokine signaling (Socs) proteins. We emphasize that common Jak-Stat-Socs signaling modules can have diverse developmental, pro- and anti-inflammatory outcomes depending on the cytokine receptor activated and which genes are accessible at a given time in a cell's life. Because multiple components of Jak-Stat-Socs pathways are mutated or closely associated with human inflammatory diseases, and cytokine-based therapies are increasingly deployed to treat inflammation, understanding cytokine signaling will continue to advance our ability to manipulate chronic and acute inflammatory diseases.

Figure 1. Cytokine signaling in T cell development and function

(A) Stat5 signaling from cytokines that use γc is essential for T cell development. Mice or humans lacking key components of this pathway (γc, Jak3, Stat5) fail to develop T cells. (B) Stat5 signaling controls the development of FoxP3-positive T regs. (C) Stat3 is crucial to the development and function of Th17 cells. IL-23 and IL-6 enforce Th17 development via the direct or indirect induction of Rorc and Rora expression. Stat3 also regulates the expression of IL-17-encoding genes and Il21, which acts in an autocrine/paracrine way to regulate Th17 cells. Socs3 is an important inhibitor of cytokines that use gp130 (IL-23R and IL-6R) while Socs1 is anticipated to inhibit any cytokines that use γc (IL-7, IL-21 as shown).

Figure 2. G-CSFR signaling

Simplified schematic of G-CSFR signaling to illustrate that Stat3 and Stat5 are regulated by the G-CSFR and that Socs3 is a key downstream target of Stat3. Socs3 is required to feedback inhibit G-CSFR signaling.

Figure 3. Mechanisms associated with Socs3-mediated suppression of anti-inflammatory signaling by the IL-6R

The left side depicts IL-10 signaling in a macrophage activated by the TLR pathway (or other similar inflammatory stimuli). Socs3 expression is strongly induced by IL-10, along with the Stat3-dependent genes whose products regulate the anti-inflammatory signaling system (‘anti-inflammatory response’ AIR gene) illustrated as inhibiting the expression at the transcriptional level of classic pro-inflammatory genes. On the right side is shown IL-6 signaling via gp130, which also activates Socs3 and other genes. Unlike the IL-10R, the IL-6R cannot activate the expression of the AIR gene(s) unless Socs3 is absent. Thus, IL-6 and IL-10 (and any other receptors that activate Socs3 expression in macrophages) enforce the inability of the IL-6R to produce the anti-inflammatory response. Note that Socs3 (or any other Socs protein) does not inhibit the IL-10R.

Figure 4. IL-22R signaling

Hypothetical schematic of tissue-specific effects of Stat3 activation by the IL-22R. In hepatocytes IL-22 activates an anti-inflammatory gene expression program while the opposite occurs in skin. Socs3 is expected to be a common target gene in each tissue.