IL-3 is a pleiotropic cytokine which plays an essential role for the differentiation of pluripotent hematopeotic stem cells into myeloid progenitor cells [29]. In an animal model of sepsis, IL-3 knockout mice showed lower mortality compared to WT mice, and had overall improved clinical scores, body temperatures, and blood pressure [29]. The WT mice had an accumulation of monocytes and neutrophils in the lungs and livers indicating higher organ injury [29]. In human studies, detectable levels of IL-3 correlated with the level of circulating monocytes in septic patients, and higher levels of IL-3 conferred poorer prognosis [29]. Inhibition of this cytokine is therefore able to indirectly decrease the amount of pro-inflammatory cytokines and reduce septic injury.

IL-7 is an immunostimulatory cytokine required for T lymphocyte development, homeostasis, and maintenance [14]. Humans who have mutations in the IL-7 gene lack T cells and have severe combined immunodeficiency (SCID) [14, 30]. In patients with sepsis, there is apoptosis -induced cell loss which contributes to immunosuppression [31]. IL-7 counteracts this by modulating the expression of pro- and anti-apoptotic members of the B cell lymphoma 2 (BCL-2) family, such as Bcl-2, Bcl-2 interacting mediator of cell death (Bim) , and p53 upregulated modulator of apoptosis (Puma) [32]. IL-7 also reverses sepsis-induced depression of T cell cytokines like interferon (IFN)-γ, which activates macrophages [14]. Additionally, IL-7 aids lymphocyte trafficking by increasing cell adhesion molecule expression via upregulation of lymphocyte function associated antigen (LFA)-1 and very late antigen (VLA)-4 [33]. Finally, IL-7 increases T cell receptor diversity that leads to a broadened response against foreign pathogens [34]. As such, IL-7 is being studied for use particularly for viral infections such as HIV and hepatitis C, and for cancer [35].

Closely related to IL-7 is IL-15, another pleuripotent cytokine that supports homeostasis, activation, and proliferation of B and T cells [14]. In contrast to IL-7, IL-15 is also essential for natural killer (NK) cell development, survival, and cell function [14]. The broad role that IL-15 has on different parts of the immune system makes IL-15 very promising as an immunotherapy agent in sepsis. Like IL-7, IL-15 treatment of septic mice decreased apoptosis of immune cells by increasing Bcl-2 expression, showing improved overall survival [36]. Against cancer, IL-15 has also shown antitumor activity in preclinical mouse tumor models [37]. In combination with blockade of other immune system checkpoints like anti-programmed cell death receptor ligand-1 (PD-L1) or anti-cytotoxic T-lymphocyte associated protein (CTLA)-4 antibodies, to be discussed later, antitumor activity was enhanced in a murine model of colon carcinoma [38].

IL-17, a pro-inflammatory cytokine, whose members includes IL-17A, -B, -C, -D, -E, and -F [39]. IL-17 is mainly produced from T helper (Th) 17 cells, yet it is also produced by other innate and adaptive immune cells which include neutrophils, lymphocytes, inducible natural killer T cells (iNK T cells), γδ T cells, and Paneth cells [39–41]. IL-17A promotes inflammation and injuries in tissues, and is known to interact predominantly with endothelial cells, epithelial cells, fibroblasts, and macrophages through binding its receptor, IL-17R thereby producing pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6 [39]. IL-17 is involved in a wide range of cellular events that include bacterial defense, rheumatoid arthritis, graft rejection, tumor modulation, and asthma and allergic reactions [42]. Although it is in these latter autoimmune processes that IL-17 has been more widely studied, IL-17 has recently attracted attention as a regulator of innate immunity in host defense. In a murine model of sepsis using cecal ligation and puncture (CLP), IL-17 was shown to promote high levels of pro-inflammatory mediators and bacteremia [42]. Levels of IL-17 increased in a time-dependent manner after CLP, and in vitro incubation of macrophages with LPS and IL-17 increased production of TNF-α, IL-1β, and IL-6 [42]. Furthermore, targeting of IL-17 with neutralizing antibodies showed a protective outcome, with reduced bacteremia and increased survival [42]. Additionally, neutralization of peritoneal IL-17 after CLP-induced sepsis resulted in markedly improved neutrophil infiltration and decreased levels of pro-inflammatory cytokine production [43]. Thus, the regulation of IL-17 expression could be beneficial in controlling inflammatory diseases. It has recently been reported that the administration of a homeostatic growth factor, milk fat globule-EGF-factor VIII (MFG-E8) during the time of CLP-mediated sepsis significantly improved the disease phenotypes [41]. Collectively, these finding reveals IL-17 to be an outstanding therapeutic target in sepsis.

The cytokine IL-22 is a member of the IL-10 superfamily (IL-19, IL-20, IL-24, and IL-26) which functions in intracellular signaling [44]. IL-22 is produced by activated dendritic cells (DCs) and T cells, and it plays a significant role in responding against bacterial pathogens, particularly in epithelial cells located in the pulmonary and intestinal mucosa [45]. In patients with sepsis, IL-22 levels were modestly elevated in the serum, likely contributing to host defense by stabilizing the mucosal barrier during infection [46]. Adverse effects, however, have also been reported in a model of polymicrobial peritonitis [47]. There is an IL-22 binding protein (IL-22BP) that modulates IL-22 activity. Treatment of mice with IL-22BP prior to sepsis led to higher infiltration of neutrophils and mononuclear phagocytes resulting in a reduced bacterial load at the site of infection [47]. Like the pathogenesis of sepsis, the role of IL-22 is complex with both pro- and anti-inflammatory components, and its duality may make it a good candidate for sepsis treatment.

IL-27 is a cytokine produced by antigen-presenting cells upon exposure to pathogenic molecules and inflammatory mediators [48, 49]. It is believed to play a role in immunosuppression, which can lead to late deaths in sepsis due to secondary infections. In one recent study, IL-27 was shown to be upregulated after an animal model of sepsis, and IL-27R KO and IL-27-neutralized mice showed improved survival, with enhanced pulmonary neutrophil recruitment [50]. They were more able to clear bacteria from the lungs of septic mice from P. aeruginosa infection , and addition of recombinant IL-27 led to increased susceptibility to infection [50]. Studies of parasitic infections in IL-27-deficient mice all exhibited enhanced pro-inflammatory responses to control parasitic replication [51]. Mechanistically, IL-27 has been shown to induce T cells production of anti-inflammatory cytokine IL-10 [52]. In human studies, IL-27 may serve as a biomarker for risk of bacterial infection in critically ill pediatric patients with systemic infections [49]. IL-27 may be an important target to reduce the immunosuppressive phase of sepsis in which people are susceptible to secondary infections .

IL-33 is the newest member of the IL-1 cytokine family. It is expressed in structural and lining cells, including fibroblastic reticular cells of lymphoid tissues, and epithelial cells [53]. At baseline, IL-33 localizes to the nucleus, but after exposure to LPS, IL-33 is released to the extracellular space [54]. IL-33 binds to its receptors, ST2 and IL-1R accessory protein, which are expressed on the surface of Th2 cells and mast cells, and this drives production of IL-5 and IL-13 via activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPK) pathways [55]. On mast cells, IL-33 triggers the production and release of pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6, promotes maturation, and induces degranulation [56]. One of the receptors, ST2, can be spliced to either a localized form bound to the cellular membrane or a soluble form. This soluble variant, sST2, can act as a decoy receptor by binding IL-33, but does not induce signaling [57]. High levels of sST2 are associated with poor prognosis in sepsis [58]. Thus, the pro-inflammatory role of IL-33 seems to be beneficial in the sepsis response, and function therapeutically to prevent mortality during the immunosuppressive phase of sepsis.

IL-35 is a newly described cytokine in the IL-12 family, which includes IL-27, an immunosuppressive cytokine discussed earlier [59]. IL-35 has been shown to be induced in the plasma of mice after LPS injection, and in the plasma of sepsis patients [59]. In addition, IL-35 decreased LPS-induced pro-inflammatory cytokines and chemokines in the plasma of mice. Levels of IL-35 in serum from septic adult or child patients were significantly higher than in healthy control, and its levels increased with severity of sepsis [60]. Mechanistically, IL-35 can inhibit LPS-induced upregulation of vascular endothelial cell adhesion molecule (VCAM)-1 via inhibition of the MAPK-mediated activator protein-1 (AP-1) signaling pathway [59]. Although IL-35 is known to be anti-inflammatory, administration of anti-IL-35 antibodies in murine sepsis significantly diminished bacterial dissemination, which was accompanied by enhanced local neutrophil recruitment and early increased release of inflammatory cytokines and chemokines [60]. Therefore, IL-35 facilitates bacterial dissemination in polymicrobial sepsis. These studies show that IL-35 plays a major role in the pathogenesis of sepsis by compromising innate immune function, though further studies of its role in early versus late phase sepsis may be valuable to delineate effects of IL-35 neutralization.

IL-36 is a cytokine that predominantly acts on naive CD4 T cells via its receptor which is a heterodimer of IL-1 receptor accessory protein (IL-1RAcP) and IL-1 receptor related protein-2 (IL-1Rrp2) [61, 62]. After binding its receptor, IL-36 activates NF-κB and MAP kinases to play a role in inflammation [61, 62]. IL-36 has also been found to activate T cell proliferation and release IL-2 [63]; thus, it may directly be involved in maintaining the functions of the innate and adaptive immune system. Although the direct role of IL-36 in sepsis is still under investigation, a recent study reports that an IL-36 receptor antagonist can ameliorate inflammation [64]. Furthermore, a new cytokine, IL-1F10 (IL-38) has been shown to be capable of inhibiting IL-36 by analogous action [65]. Thus, the growing body of evidence in this new innate immune field is promising in understanding sepsis pathophysiology and developing potential therapeutic interventions.

IL-37, formerly IL-1 family member 7, is a protein that is encoded in humans by the IL1F7 gene, and functions to downregulate inflammation [66]. Expression of IL-37 in macrophages or epithelial cells almost completely suppresses production of pro-inflammatory cytokines, while silencing of endogenous IL-37 leads to increased cytokine production in human blood cells [67]. IL-37 transgenic mice were protected from endotoxin-induced shock, and showed remarkable improvement of lung and kidney function, and reduced liver damage after treatment with endotoxin [67]. Transgenic mice containing the human IL-37 gene had significantly reduced levels of systemic and tissue cytokines compared to wild-type mice by reducing dendritic cell activation [67]. IL-37 interacts with the transcription factor, Smad3, and under Smad3-deficient conditions, neither IL-37-expressing cells nor transgenic mice were able to show suppression of cytokine expression [67]; thus IL-37 emerges as a natural suppressor of innate inflammatory and immune responses.

Granulocyte-macrophage-colony-stimulating factor (GM-CSF), a 23-kD growth factor, exhibits potent immunostimulatory effects on a variety of innate immune cells [68]. It promotes host defense against invading pathogens by improving survival, proliferation, differentiation, phagocytosis, and bacterial killing of neutrophils and monocytes/macrophages [68]. GM-CSF has been shown to increase HLA-DR expression and endotoxin-induced pro-inflammatory cytokine production in whole blood cultures of patients with severe sepsis under an ex vivo condition [69]. In order to define its role in sepsis, it has been demonstrated that GM-CSF secreted from a distinct type of B lymphocyte protects mice against polymicrobial sepsis [70]. Additionally, a recent clinical trial reported that administration of GM-CSF successfully reversed long-lasting monocyte deactivation (anergy) in sepsis [71]. In a multicenter, prospective, randomized, double-blind, placebo-controlled trial examining patients with severe sepsis or septic shock and sepsis-associated immunosuppression, GM-CSF has been shown to be protective by shortening the time of mechanical ventilation and hospital stay [72]. Thus, GM-CSF serves as a safe and effective therapeutic potential for restoring monocytic functions in sepsis.