The transcription factor NF-kappaB has been the focus of intense investigation for nearly two decades. Over this period, considerable progress has been made in determining the function and regulation of NF-kappaB, although there are nuances in this important signaling pathway that still remain to be understood. The challenge now is to reconcile the regulatory complexity in this pathway with the complexity of responses in which NF-kappaB family members play important roles. In this review, we provide an overview of established NF-kappaB signaling pathways with focus on the current state of research into the mechanisms that regulate IKK activation and NF-kappaB transcriptional activity.

/pdf/signaling-to-nf-kappab-1zyb7vgt7s.pdf

Signaling to NF-kappaB.

https://molmed.nl/uploads/abstracts/158/il-33 discovery.pdf

IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines

More than any other cytokine family, the interleukin (IL)-1 family is closely linked to the innate immune response. This linkage became evident upon the discovery that the cytoplasmic domain of the IL-1 receptor type I is highly homologous to the cytoplasmic domains of all Toll-like receptors (TLRs). Thus, fundamental inflammatory responses such as the induction of cyclooxygenase type 2, increased expression of adhesion molecules, or synthesis of nitric oxide are indistinguishable responses of both IL-1 and TLR ligands. Both families nonspecifically affect antigen recognition and lymphocyte function. IL-1β is the most studied member of the IL-1 family because of its role in mediating autoinflammatory diseases. Although the TLR and IL-1 families evolved to assist in host defense against infection, unlike the TLR family, the IL-1 family also includes members that suppress inflammation, both specifically within the IL-1 family but also nonspecifically for TLR ligands and the innate immune response.

Immunological and Inflammatory Functions of the Interleukin-1 Family

Neutrophils are innate immune phagocytes that have a central role in immune defence. Our understanding of the role of neutrophils in pathogen clearance, immune regulation and disease pathology has advanced dramatically in recent years. Web-like chromatin structures known as neutrophil extracellular traps (NETs) have been at the forefront of this renewed interest in neutrophil biology. The identification of molecules that modulate the release of NETs has helped to refine our view of the role of NETs in immune protection, inflammatory and autoimmune diseases and cancer. Here, I discuss the key findings and concepts that have thus far shaped the field of NET biology.

Neutrophil extracellular traps in immunity and disease

The Interleukin-1 Family: Back to the Future

An interesting trait shared by many members of the IL-1 cytokine family is the absence of a signal sequence that can direct the newly synthesized polypeptides to the endoplasmic reticulum. As a result, these cytokines accumulate intracellularly. Recent studies investigating IL-1β export established that its release is facilitated via activation of an intracellular multiprotein complex termed the inflammasome. The purpose of the current study was to explore the mechanism by which murine IL-1F6 is released from bone marrow-derived macrophages (BMDMs) and to compare this mechanism to that used by IL-1β. BMDMs were engineered to overexpress IL-1F6 by retroviral transduction; cells overexpressing GFP also were generated to provide a noncytokine comparator. The transduced cells constitutively expressed IL-1F6 and GFP, but they did not constitutively release these polypeptides to the medium. Enhanced release of IL-1F6 was achieved by treating with LPS followed by ATP-induced activation of the P2X 7 receptor; GFP also was released under these conditions. No obvious proteolytic cleavage of IL-1F6 was noted following P2X 7 receptor-induced release. Stimulus-induced release of IL-1F6 and GFP demonstrated comparable susceptibility to pharmacological modulation. Therefore, transduced IL-1F6 is released in parallel with endogenous mature IL-1β from LPS/ATP-treated BMDMs, but this externalization process is not selective for cytokines as a noncytokine (GFP) shows similar behavior. These findings suggest that IL-1F6 can be externalized via a stimulus-coupled mechanism comparable to that used by IL-1β, and they provide additional insight into the complex cellular processes controlling posttranslational processing of the IL-1 cytokine family.

/pdf/externalization-of-the-leaderless-cytokine-il-1f6-occurs-in-cyklh9riih.pdf

Externalization of the Leaderless Cytokine IL-1F6 Occurs in Response to Lipopolysaccharide/ATP Activation of Transduced Bone Marrow Macrophages

IL-1Rrp2 expression and IL-1F9 (IL-1H1) actions in brain cells.

The interleukin-1-related cytokine IL-1F8 is expressed in glial cells, but fails to induce IL-1β signalling responses

A Single Amino Acid Difference between Human and Monkey Interleukin (IL)-1β Dictates Effective Binding to Soluble Type II IL-1 Receptor

The invention is directed to novel, purified and isolated IL-1 eta polypeptides and fragments thereof, the polynucleotides encoding such polypeptides, processes for production of recombinant forms of such polypeptides, antibodies generated against these polypeptides, peptides derived from these polypeptides, and uses thereof.

Blair R. Renshaw

Papers

Externalization of the Leaderless Cytokine IL-1F6 Occurs in Response to Lipopolysaccharide/ATP Activation of Transduced Bone Marrow Macrophages

IL-1Rrp2 expression and IL-1F9 (IL-1H1) actions in brain cells.

The interleukin-1-related cytokine IL-1F8 is expressed in glial cells, but fails to induce IL-1β signalling responses

A Single Amino Acid Difference between Human and Monkey Interleukin (IL)-1β Dictates Effective Binding to Soluble Type II IL-1 Receptor

Il-1 eta DNA and polypeptides