Inflammatory conditions in selected organs increase the risk of cancer. An inflammatory component is present also in the microenvironment of tumors that are not epidemiologically related to inflammation. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. In the tumor microenvironment, smoldering inflammation contributes to proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, reduced response to hormones and chemotherapeutic agents. Recent data suggest that an additional mechanism involved in cancer-related inflammation (CRI) is induction of genetic instability by inflammatory mediators, leading to accumulation of random genetic alterations in cancer cells. In a seminal contribution, Hanahan and Weinberg [(2000) Cell, 100, 57-70] identified the six hallmarks of cancer. We surmise that CRI represents the seventh hallmark.

Interleukin-1 (IL-1) is a central mediator of innate immunity and inflammation. The IL-1 family includes 7 ligands with agonist activity (IL-1α and β, IL-18, IL-33, IL-36α, β, γ), three receptor antagonists (IL-1Ra, IL-36Ra, IL-38) and an anti-inflammatory cytokine (IL-37). Members of the IL-1 Receptor (IL-1R) family include 6 receptor chains forming 4 signaling receptor complexes, two decoy receptors (IL-1R2, IL-18BP) and two negative regulators (TIR8 or SIGIRR, IL-1RAcPb). A tight regulation via receptor antagonists, decoy receptors and signaling inhibitors ensures a balance between amplification of innate immunity and uncontrolled inflammation. All cells of the innate immune system express and/or are affected by IL-1 family members. Moreover, IL-1 family members play a key role in the differentiation and function of polarized innate and adaptive lymphoid cells. Here we will review the key properties of IL-1 family members, with emphasis on pathways of negative regulation and orchestration of innate and adaptive immunity.

C reactive protein, the first innate immunity receptor identified, and serum amyloid P component are classic short pentraxins produced in the liver. Long pentraxins, including the prototype PTX3, are expressed in a variety of tissues. Some long pentraxins are expressed in the brain and some are involved in neuronal plasticity and degeneration. PTX3 is produced by a variety of cells and tissues, most notably dendritic cells and macrophages, in response to Toll-like receptor (TLR) engagement and inflammatory cytokines. PTX3 acts as a functional ancestor of antibodies, recognizing microbes, activating complement, and facilitating pathogen recognition by phagocytes, hence playing a nonredundant role in resistance against selected pathogens. In addition, PTX3 is essential in female fertility because it acts as a nodal point for the assembly of the cumulus oophorus hyaluronan-rich extracellular matrix. Thus, the prototypic long pentraxin PTX3 is a multifunctional soluble pattern recognition receptor at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility.

Innate lymphoid cells (ILC)-22 protect the intestinal mucosa from infections by secreting interleukin-22 (IL-22). They include NKp46+ and Lymphoid Tissues inducer (LTi)-like subsets. Both express the aryl-hydrocarbon receptor (AHR), a sensor for environmental, dietary and endogenous aromatic compounds. We show that AHR-/- mice have a marked ILC22 deficit, resulting in diminished IL-22 secretion and inadequate protection against intestinal bacterial infections. AHR-/- mice also lack post-natally-imprinted cryptopatches (CP) and isolated lymphoid follicles (ILF), but not embryonically-imprinted Peyer's Patches (PP). AHR induces Notch, which is required for NKp46+ILC, while LTi-like ILC, CP and ILF are partially dependent on Notch signaling. These results establish that AHR is essential for ILC22 and post-natal intestinal lymphoid tissues and reveal heterogeneity of ILC22 subsets in their developmental requirements and their impact on the generation of intestinal lymphoid tissues.