Table I. Variables associated with pancreatic cancer risk via inflammatory pathways.

Inflammatory mediators	Regulation and Role	Association with PC risk factors and PC
Nuclear factor Kappa B (NF-κB)	Transcriptional regulator activated by ROS, hypoxia, cytokines, bacterial/viral products, and UV radiation. Stimulates the expression of IL-1β, TNF-α, iNOS, COX-2 thus amplifying inflammatory response in tumor environment	Activated during AP, CP, and MS and play central role during inflammation. By interacting with RAS oncogene, it is involved in initiation and progression of PC [18, 22, 30, 82-84]
Signal transducer and activator of transcription 3 (STAT3)	Transcription factor, act as convergence point for various cytokine, growth factor pathways and mediates response to inflammation, cell proliferation and apoptosis	During pancreatitis, STAT3 regulates increased expression of MMP7 in PanINs and PDACs causing increased proliferation, metastasis and decreased apoptosis [73, 74, 85, 86].
Cyclooxygenase-2 (COX-2)	Prostaglandin synthesizing inducible enzyme activated by cytokines/ growth factors, mediating immunologic surveillance, cell differentiation, proliferation, anti-apoptosis, and metastasis.	Converts chemical carcinogens of tobacco smoke to mutagenic derivatives. Elevated during pancreatitis, obesity, IR and PC [53, 87-91].
Neutrophil gelatinase associated lipocalin (NGAL)	Acute phase secretory glycoprotein regulated by pro-inflammatory cytokines, interferons and retinoic acid. Elevated during type-2 diabetes, chronic and severe acute pancreatitis (SAP).	Predicts multiorgan failure and fatal outcome in patients with SAP. Highly expressed in early dysplastic lesions in the pancreas [92, 93].
Tumor necrosis factor-alpha (TNF-α)	Pro-inflammatory cytokine secreted by activated macrophages, CD4+ lymphocytes, NK cells mediating acute phase reaction, acting as a potent chemo- attractant of neutrophils and promotes secretion of IL-1 oxidants and inflammatory prostaglandins from macrophages.	Central point during inflammatory reaction. Activates NF-κB and c-JUN signaling, growth, differentiation, survival and apoptosis. Significantly increased TNF-α level are found in CP, obese individuals, and PC patients. Involved in development of IR and associated with activation of pancreatic stellate cells [12, 40, 59, 78].
Interleukin 1β (IL-1β)	Pro-inflammatory cytokine secreted by activated macrophages and malignant cells. Act as lymphocyte mitogen and mediates inflammatory response, cell proliferation, differentiation and apoptosis.	Key contributor to the obesity-induced inflammation and subsequent IR, induced by fat necrosis in AP and results in NF-κB and JNK signaling mediated increased invasion and angiogenesis of PC cells [94, 95].
Interleukin-6 (IL-6)	Pro- and anti-inflammatory cytokine secreted by T-cells and macrophages, adipocytes and involved in mediating acute phase response and activating immune response.	Activates JAK - STAT kinases. Elevated during smoking, obesity, diabetes, CP and PC [33, 38, 96, 97].
Transforming growth factor-beta (TGF-β)	Cytokine regulated by ROS, proteases and Integrin. Involved in recruitment of monocytes, macrophages, NK cells, neutrophils and T cells and mediates cell proliferation, differentiation, angiogenesis and wound healing.	Elevated levels in chronic pancreatitis are associated with increased fibrosis in pancreas. Systemic blockade of TGF-β signaling protects mice from obesity and diabetes. Induces epithelial to mesenchymal transition (EMT) and angio- genesis to promote PC progression [13, 51, 98-100].
Peroxisome proliferator- activated receptor-γ (PPAR-γ)	Ligand dependent transcription factor involved in differentiation of immune cells towards anti-inflammatory phenotypes. Regulate adipocyte differentiation, fatty acid storage and glucose metabolism, and is a target of anti-diabetic drugs.	Drugs of the thiazolidinedione family activate PPAR-γ to inhibit PC cell growth by inhibition of COX2, NF-κB and angiogenic factor VEGF [75, 101-104].
Reactive oxygen species (ROS)	Chemically reactive molecules containing oxygen with unpaired valence shell electrons. Imbalance of oxidants and antioxidants cause oxidative stress (OS) that results in DNA damage, inflammation by activating NF-κB.	Increased ROS and lipid peroxidation is observed during MS, smoking, obesity, CP and PC [105-108].

AP: acute pancreatitis; CD4⁺,cluster of differentiation 4⁺; CP: chronic pancreatitis; EMT: epithelial mesenchymal transition; iNOS: inducible nitric oxide synthase; IR: insulin resistance; JNK: c-Jun N-terminal kinase; MMP7: matrix metalloproteinase7; MS: metabolic syndrome; NK cells: natural killer cells; OS: oxidative stress; PanIN: pancreatic intraepithelial neoplasia; PC: pancreatic cancer; PDAC: pancreatic ductal adenocarcinoma; ROS: reactive oxygen species; SAP: severe acute pancreatitis; UV: ultra violet; VEGF: vascular endothelial growth factor.