title: Interleukin 6, but not T helper 2 cytokines, promotes lung carcinogenesis.
abstract: Several epidemiologic studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer compared with smokers without COPD. We have shown a causal role for COPD-like airway inflammation in lung cancer promotion in the CCSP(Cre)/LSL-K-ras(G12D) mouse model (CC-LR). In contrast, existing epidemiologic data do not suggest any definite association between allergic airway inflammation and lung cancer. To test this, CC-LR mice were sensitized to ovalbumin (OVA) and then challenged with an OVA aerosol weekly for 8 weeks. This resulted in eosinophilic lung inflammation associated with increased levels of T helper 2 cytokines and mucous metaplasia of airway epithelium, similar to what is seen in asthmatic patients. However, this type of inflammation did not result in a significant difference in lung surface tumor number (49 ± 9 in OVA vs. 52 ± 5 in control) in contrast to a 3.2-fold increase with COPD-like inflammation. Gene expression analysis of nontypeable Haemophilus influenzae (NTHi)-treated lungs showed upregulation of a different profile of inflammatory genes, including interleukin 6 (IL-6), compared with OVA-treated lungs. Therefore, to determine the causal role of cytokines that mediate COPD-like inflammation in lung carcinogenesis, we genetically ablated IL-6 in CC-LR mice. This not only inhibited intrinsic lung cancer development (1.7-fold) but also inhibited the promoting effect of extrinsic COPD-like airway inflammation (2.6-fold). We conclude that there is a clear specificity for the nature of inflammation in lung cancer promotion, and IL-6 has an essential role in lung cancer promotion.
authors.affiliation: Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, Houston, TX 77030, USA.
authors.forename: Cesar E
authors.initials: CE
authors.lastname: Ochoa
authors.forename: Seyedeh Golsar
authors.initials: SG
authors.lastname: Mirabolfathinejad
authors.forename: Venado Ana
authors.initials: VA
authors.lastname: Ruiz
authors.forename: Scott E
authors.initials: SE
authors.lastname: Evans
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Evans
authors.forename: Burton F
authors.initials: BF
authors.lastname: Dickey
authors.forename: Seyed Javad
authors.initials: SJ
authors.lastname: Moghaddam
mesh_terms: D000336:Aerosols; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D006192:Haemophilus Infections / Q000276:immunology / Q000382:microbiology; D006193:Haemophilus influenzae / Q000472:pathogenicity; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D015850:Interleukin-6 / Q000502:physiology*; D008175:Lung Neoplasms / Q000209:etiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010047:Ovalbumin / Q000494:pharmacology; D011014:Pneumonia / Q000276:immunology / Q000382:microbiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000382:microbiology / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D018418:Th2 Cells / Q000276:immunology*; D047368:Tumor Burden; D014598:Uteroglobin / Q000235:genetics
chemical_list: D000336:Aerosols; D014408:Biomarkers, Tumor; D016207:Cytokines; D015850:Interleukin-6; D012333:RNA, Messenger; C556390:Scgb1a1 protein, mouse; D010047:Ovalbumin; D014598:Uteroglobin; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)